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From Bruce K. Cassels, Alkaloids from the Genus Duguetia. In: Geoffrey A. Cordell, editors, The
Alkaloids. Chennai: Academic Press, 2010, pp. 83-156.
ISBN: 978-0-12-381335-0
© Copyright 2010 Elsevier Inc.
Academic Press.
Author’s personal copy
CHAPT ER
3
Alkaloids from the Genus
Duguetia
Edwin G. Pérez1,3,w and Bruce K. Cassels2,3,*
Contents
I. Introduction
II. Botanical Considerations
III. Alkaloids from Chemically Investigated Duguetia species
A. Benzyltetrahydroisoquinolines
B. Bisbenzyltetrahydroisoquinolines
C. Berbines and Protoberberines
D. Morphinandienone
E. Aporphinoids
F. Miscellaneous Aporphinoid- and Berbinoid-Related
Alkaloids
IV. Structure and Chemistry
A. Benzyltetrahydroisoquinolines
B. Bisbenzyltetrahydroisoquinoline
C. Berbinoids
D. Morphinandienone
E. Aporphinoids
F. Miscellaneous Aporphinoid- and Berbinoid-Related
Alkaloids
V. Biosynthesis, Biogenesis, and Chemosystematics
VI. Ethnopharmacology and Pharmacology
A. Benzyltetrahydroisoquinolines
B. Bisbenzylisoquinoline
C. Berbinoids
1
Department of Chemistry, Faculty of Chemistry and Biology, University of Santiago, Santiago, Chile
2
Department of Chemistry, Faculty of Sciences, University of Chile, Chile
3
w
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Millennium Institute for Cell Dynamics and Biotechnology, Santiago, Chile
Present address: Facultad de Quı́mica, Pontificia Universidad Católica de Chile, Santiago, Chile
*
Corresponding author.
E-mail address: bruce.cassels@gmail.com (B.K. Cassels)
The Alkaloids, Volume 68
ISSN: 1099-4831, DOI 10.1016/S1099-4831(10)06803-3
r 2010 Elsevier Inc.
All rights reserved
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Edwin G. Pérez and Bruce K. Cassels
D. Protoberberines
E. Glaziovine
F. Aporphines
G. Oxoaporphines
H. Aminoethylphenanthrenes
I. Copyrine Alkaloids
J. 1-Aza-9,10-anthraquinones
VII. Concluding Remarks
Acknowledgments
References
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I. INTRODUCTION
Duguetia A. St.-Hil. (Annonaceae) is a genus of usually small, understory
trees growing almost exclusively in the tropics of South America, with a
small extension across the Panama Isthmus. It is now regarded as
comprising close to 100 species, considering the recent inclusion of four
African taxa, of which three were previously known as Pachypodanthium
Engler & Diels. It is therefore one of the largest Annonaceous genera after
Guatteria and Annona. Many studies have been conducted on the
secondary metabolites present in different parts of Duguetia plants, from
which essential oils, aromatic compounds, monoterpenes, diterpenes,
triterpenes, flavonoids, and most typically alkaloids have been isolated
and characterized. In common with the other ‘‘primitive angiosperms,’’
Duguetia species accumulate isoquinoline alkaloids, and more specifically
1-benzyl-1,2,3,4-tetrahydroisoquinolines, usually referred to simply as
‘‘benzylisoquinolines,’’ and their biosynthetic or biogenetically presumed
derivatives. The literature reports studies on the alkaloids of about 16
Duguetia species (one of which was not clearly identified), resulting in the
isolation and identification or characterization of 105 different alkaloids.
Although many of these alkaloids are widely distributed, a few unusual
groups of alkaloids appear to be specific to this genus.
II. BOTANICAL CONSIDERATIONS
The plants of the Annonaceae have traditionally been classed as part of
the order Magnoliales. In the most recent consensus, the Magnoliales and
Laurales constitute one of the two sister clades in the Magnoliidae, which
are commonly regarded as the most ‘‘primitive’’ angiosperms in older
classifications (1,2).
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Alkaloids from the Genus Duguetia
85
Regarding the occurrence of benzylisoquinoline alkaloids in the
Annonaceae, other magnoliids, and more distantly related families, it
is of interest to note that there is now good biochemical and
molecular phylogenetic evidence for the evolution of benzylisoquinoline alkaloid biosynthesis in angiosperms from a common ancestor.
Activity ascribable to the first enzyme in this biosynthetic tree,
(S)-norcoclaurine synthase, occurs in 90 different plant species, and
compares well with a molecular phylogeny. Phylogenetic analyses of
norcoclaurine synthase, the berberine bridge enzyme, and several
O-methyltransferases ‘‘suggest a latent molecular fingerprint for
benzylisoquinoline alkaloid biosynthesis in angiosperms not known
to accumulate such alkaloids’’ (3).
Duguetia was thought, on the basis of inflorescence and floral
characters, to form an alliance with the very small neotropical genera
Duckeanthus, Fusaea, and Malmea, and the African Letestudoxa (4). The
monotypic Pseudartabotrys was later included and Malmea excluded (5),
but incorporation of leaf, flower, fruit, and seed characters that had not
been considered previously has led to a different grouping in which
Duguetia (including Pachypodanthium) constitutes a clade of its own, close
to a separate sister group including Fusaea, Duckeanthus, Letestudoxa, and
Pseudartabotrys (6). Despite the inclusion of Pachypodanthium as ‘‘African
species of Duguetia,’’ these plants still form a small, distinct cluster,
perhaps not surprisingly together with Duguetia riberensis of Venezuela,
in this cladistic analysis.
The genus has been further subdivided into 14 sections by Fries
based on their morphological characters, but leaving some species in
uncertain positions (7,8). These subdivisions have largely been upheld
by a more recent study (9), and it is the system used in this review
(Table I).
One third of all Duguetia species were analyzed in a study based
on their genomic DNA sequences (41). That work supported the notion
that Duguetia, like Guatteria, is monophyletic, with its most recent
common ancestor dating back to 29.0474.52 million years ago (in the
case of Guatteria this figure is 36.6572.50 mybp), although the authors
concede that ‘‘the accuracy of the absolute dates remains unassessed.’’
A fossilized leaf from the middle Eocene period (about 38 48 mybp)
from Western Tennessee, when the local climate was subtropical to
tropical, has been classified as belonging to a Duguetia species (42), a
conclusion that seems to conflict with the estimated DNA age of the
genus. On the basis of its present geographic, trans-Atlantic distribution it was suggested that the Duguetia clade might predate the
break-up of Gondwana (6). As the separation of Africa and South
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Edwin G. Pérez and Bruce K. Cassels
America is believed to have been completed in the early Cretaceous
(about 110 million years ago), and the age of the Annonaceae as a family
is estimated to be as little as 82 million years (43), it seems necessary to
assume long-distance dispersal over the widening early Atlantic Ocean,
possibly across stepping-stones along the 80 million-year-old
volcanic Sierra Leone Rise (to which the Ceará Rise should be
added) (44) or, less likely, the more southerly Walvis Ridge (and Rio
Grande Rise) (45). This hypothesis seems reasonable given the
presence of Annonaceae in the Lesser Antilles, which would represent
much more recent (Pliocene or even Pleistocene) events of a similar
character (46).
III. ALKALOIDS FROM CHEMICALLY INVESTIGATED
DUGUETIA SPECIES
The Duguetia species studied to date for their alkaloidal content are
listed in Table I, ordered by sections, and in alphabetical order when
appropriate. All of the alkaloids isolated from this genus have at least a
formal isoquinoline-derived structure; including the 1-azaanthraquinone cleistopholine and the rare copyrine alkaloids, the 1-aza-7oxoaporphines and 1-aza-4,5-dioxoaporphines. These alkaloids are
classified as benzyltetrahydroisoquinolines, a single bisbenzyltetrahydroisoquinoline, berbines (tetrahydroprotoberberines), protoberberines,
a morphinandienone, a proaporphine, and many aporphinoids and
aporphinoid-related compounds. A large proportion of the aporphines
are oxygenated at C7, a fairly common feature in the Annonaceae.
7-Methoxy derivatives are almost completely restricted to the African
Duguetia species. Four N-formylnoraporphines have been identified.
Three nitroso- or nitroaporphinoid derivatives isolated from Duguetia
furfuracea might be artifacts, as discussed below. Several of the
aporphinoids have the unusual 9,11-dioxygenation pattern in ring D
which, aside from Duguetia, has only been found in one Guatteria
species. As in Guatteria, some of the Duguetia aporphinoids bear a
biogenetically intriguing carbon atom bonded to C7. Finally, a
protoberberine styrene adduct is a unique alkaloid from the African
Duguetia staudtii. Table II lists the 105 alkaloids, including some
possible artifacts, ordered according to their main structural features, as
depicted in Figure 1 (Table III).
In many cases, the structures were known prior to their isolation
from Duguetia species, or were very closely related to known alkaloids,
Author’s personal copy
Table I
Chemically investigated Duguetia species and their contained alkaloids
Alkaloid
Duguetia R. E. Fries
D. furfuracea (A. St.-Hil.)
Benth. & Hook.
Reticuline
Isochondodendrine
Discretamine
Isocorydine
Norisocorydine
Xylopine
Obovanine
Anonaine
Asimilobine
Atherospermidine
Liriodenine
Lanuginosine
Duguetine
N-Oxyduguetine
Dicentrinone
N-Methylglaucine
N-Methyl-tetrahydropalmatine
N-Nitrosoanonaine
N-Nitrosoxylopine
8-Nitroisocorydine
Dehydrodiscretine
Pseudopalmatine
Oliveroline
N-Methylguatterine
D. odorata (Diels) J. F. Macbr.
Structure
1
3
4
41
40
28
30
23
20
86
83
87
76
77
91
36
8
51
52
42
16
17
60
66
Ref.(s)
10
10
10
10
10
10
10
10
10
10
10
10
11
11
11
11
11
12
12
13
14
14
14
14
87
Species
Alkaloids from the Genus Duguetia
Section
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88
Table I (Continued)
Section
Alkaloid
Structure
Ref.(s)
D. stelechantha (Diels) R. E. Fries
Oxopukateine
O-Methylmoschatoline
Corypalmine
Hadranthine A
Hadranthine B
Imbiline-1
Sampangine
3-Methoxysampangine
Discretamine
10-Demethylxylopinine
Xylopine
Puterine
O-Methylpukateine
Obovanine
Oxoputerine
Atherosperminine
Calycinine
Noratherosperminine
Duguecalyne
N-Formylputerine
Duguenaine
Xylopine
Isolaureline
88
85
5
99
100
101
97
98
4
11
28
31
32
30
89
94
43
93
54
53
47
28
29
15
15
15
16
16
16
16
16
17
17
17
17
17
17
17
17
17
18
19
19
20
20
20
Hadrantha R. E. Fries
D. hadrantha (Diels) R. E. Fries
Sphaerantha R. E. Fries
D. calycina Benoist
D. obovata R. E. Fries
Edwin G. Pérez and Bruce K. Cassels
Species
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48
33
34
49
27
43
44
45
50
46
90
12
10
18
2
21
67
68
70
56
58
59
73
74
71
72
89
20
20
20
20
20
20
20
20
20
20
20
20
20
20
21,22
21
21
21
21
21
21
21
21
21
21
21
Alkaloids from the Genus Duguetia
D. spixiana Mart. (Colombia)
N-Formylxylopine
Buxifoline
N-Methylbuxifoline
N-Formylbuxifoline
Anolobine
Calycinine
N-Methylcalycinine
Duguevanine
N-Formylduguevanine
N-Methylduguevanine
Oxobuxifoline
Xylopinine
Discretine
(9S)-Sebiferine
N-Oxycodamine
N-Methylasimilobine
Noroliveridine
Oliveridine
N-Oxyoliveridine
Norpachyconfine
Pachyconfine
N-Oxypachyconfine
Spixianine
N-Oxyspixianine
Duguexine
N-Oxyduguexine
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Table I (Continued)
Section
Species
Structure
Ref.(s)
Lanuginosine
Atherosperminine
N-Oxyatherosperminine
Methoxyatherosperminine
Spiduxine
Duguespixine
Anonaine
Nornuciferine
3-Hydroxynornuciferine
O-Methylisopiline
Noroliveridine
Oliveridine
N-Oxyoliveridine
Duguexine
Roemerolidine
Nornuciferidine
Rurrebanine
Rurrebanidine
Lysicamine
Lanuginosine
O-Methylmoschatoline
Spiguetidine
87
94
95
96
13
55
23
22
25
26
67
68
70
71
69
57
63
62
84
87
85
103
21
21
21
21
21
21,23
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
Edwin G. Pérez and Bruce K. Cassels
D. spixiana Mart. (Bolivia)
Alkaloid
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D. vallicola J. F. Macbr.
Polyantha R. E. Fries
D. eximia Diels
Geanthemum R. E. Fries
D. flagellaris Huber
102
12
7
37
41
38
68
60
92
85
12
10
17
104
19
85
88
89
22
24
26
43
45
78
60
24
24
24
25
26
26
27
27
27
27
26
26
26
27
26
28
28
28
29,30
29,30
29,30
29,30
29,30
29,30
29,30
Alkaloids from the Genus Duguetia
Calothrix R. E. Fries
Spiguetine
Xylopinine
Tetrahydropalmatine
N-Methyllaurotetanine
Isocorydine
Isoboldine
Oliveridine
Oliveroline
Duguevalline
O-Methylmoschatoline
Xylopinine
Discretine
Pseudopalmatine
Cleistopholine
Glaziovine
O-Methylmoschatoline
Oxopukateine
Oxoputerine
Nornuciferine
Isopiline
O-Methylisopiline
Calycinine
Duguevanine
Pachypodanthine
Oliveroline
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Table I (Continued)
Section
D. colombiana Maas
D. gardneriana Mart.
D. glabriuscula R. E. Fries
D. magnolioidea Maas
D. trunciflora Maas
Undetermined
Duguetia sp.
African species
D. confinis
(Engl. & Diels) Chatrou
Alkaloid
N-Oxyoliveroline
Oliveridine
Duguetine
O-Methylmoschatoline
Discretamine
Corypalmine
Tetrahydropalmatine
Polyalthine
Oliveridine
Oxobuxifoline
Lanuginosine
Discretamine
Reticuline
Tetrahydropalmatine
Corypalmine
Discretamine
Thaicanine
Jatrorrhizine
Norglaucine
Dicentrine
Duguetine
Corypalmine
Isocorypalmine
Structure
61
68
76
85
4
5
7
75
68
90
87
4
1
7
5
4
14
15
35
39
76
5
6
Ref.(s)
29,30
29,30
29,30
31
32
32
32
33
33
33
33
34
35
35
35
35
35
35
36
36
36
37
37
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Uncertain
Species
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D. staudtii
(Engl. & Diels) Chatrou
7
9
10
60
64
65
58
78
80
5
6
10
79
82
81
83
105
78
37
38
38
37
37
37
37
38
38
39
40
39
39
39
39
39,40
39,40
39,40
Alkaloids from the Genus Duguetia
Tetrahydropalmatine
Govanine
Discretine
Oliveroline
Guatterine
N-Oxyguatterine
Pachyconfine
Pachypodanthine
N-Acetylpachypodanthine
Corypalmine
Isocorypalmine
Discretine
N-Methylpachypodanthine
Pachystaudine
Norpachystaudine
Liriodenine
Staudine
Pachypodanthine
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Table II Alkaloids isolated from Duguetia species
Alkaloid type and name
MW
Species
Ref.(s)
1
C19H23NO4
329
cis-N-Oxycodamine
2
C20H25NO5
359
D. furfuracea
D. trunciflora
D. spixianaa
10
35
21,22
Bisbenzylisoquinoline
Isochondodendrine
3
C36H28N2O6
594
D. furfuracea
10
Berbines (Tetrahydroprotoberberines)
( )-Discretamine
4
C19H21NO4
327
( )-Corypalmine (Tetrahydrojatrorrhizine)
5
C20H23NO4
341
( )-Isocorypalmine
6
C20H23NO4
341
( )-Tetrahydropalmatine (Rotundine)
7
C21H25NO4
355
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
17
32
10
35
34
32
15
35
39
37
40
37
37
24
32
35
calycina
gardneriana
furfuracea
trunciflora
magnolioidea
gardneriana
stelechantha
trunciflora
staudtii
confinis
staudtii
confinis
confinis
spixianab
gardneriana
trunciflora
Edwin G. Pérez and Bruce K. Cassels
Molecular formula
Benzylisoquinolines
(þ)-Reticuline
Structure
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C22H28NO4
C20H23NO4
C20H23NO4
370
341
341
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
furfuracea
confinis
obovata
vallicola
confinis
staudtii
calycina
obovata
spixianab
vallicola
spixianaa
trunciflora
11
38
20
26
38
39
17
20
24
26
21
35
( )-10-Demethylxylopinine
( )-Xylopinine
11
12
C20H23NO4
C21H25NO4
341
355
( )-Spiduxine
( )-Thaicanine
13
14
C21H23NO5
C21H25NO5
369
371
Protoberberines
Jatrorrhizine
Dehydrodiscretine
Pseudopalmatine
15
16
17
C20H20NO4
C20H20NO4
C21H22NO4
338
338
352
D.
D.
D.
D.
trunciflora
odorata
odorata
vallicola
35
14
14
26
Morphinandienone
(9S)-Sebiferine
18
C20H23NO4
341
D. obovata
20
Proaporphine
( )-Glaziovine
19
C18H19NO3
297
D. vallicola
26
Aporphines sensu stricto
Asimilobine
N-Methylasimilobine
20
21
C17H17NO2
C18H19NO2
267
281
D. furfuracea
D. spixianaa
10
21
95
8
9
10
Alkaloids from the Genus Duguetia
N-Methyltetrahydropalmatine
( )-Govanine
( )-Discretine
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Table II (Continued)
Alkaloid type and name
Structure
MW
Species
Ref.(s)
D. spixianab
D. flagellaris
D. spixianab
D. furfuracea
D. flagellaris
D. spixianab
D. spixianab
D. flagellaris
D. obovata
D. calycina
D. obovata
D. furfuracea
D. obovata
D. calycina
D. furfuracea
D. calycina
D. calycina
D. obovata
D. obovata
Duguetia sp.
D. furfuracea
D. vallicola
D. vallicola
24
29,30
24
10
29,30
24
24
29,30
20
17
20
10
20
17
10
17
17
20
20
36
11
25
26
Nornuciferine
22
C18H19NO2
281
Anonaine
23
C17H15NO2
265
Isopiline
3-Hydroxynornuciferine
O-Methylisopiline
24
25
26
C18H19NO3
C18H19NO3
C19H21NO3
297
297
311
Anolobine
Xylopine
27
28
C17H15NO3
C18H17NO3
281
295
Isolaureline
Obovanine
29
30
C19H10NO3
C17H15NO3
309
281
Puterine
O-Methylpukateine
Buxifoline
N-Methylbuxifoline
Norglaucine
N-Methylglaucine
N-Methyllaurotetanine
Isoboldine
31
32
33
34
35
36
37
38
C18H17NO3
C19H19NO3
C19H19NO4
C20H21NO4
C20H23NO4
C22H28NO4
C20H23NO4
C19H21NO4
295
309
325
339
341
370
341
327
Edwin G. Pérez and Bruce K. Cassels
Molecular formula
Author’s personal copy
36
10
10
26
13
17
29,30
20
20
20
29,30
20
C19H17NO4
C19H17NO4
C20H19NO5
C20H21NO6
323
323
353
369
D.
D.
D.
D.
calycina
obovata
obovata
obovata
19
20
20
20
51
52
C17H14N2O3
C18H16N2O4
294
324
D. furfuracea
D. furfuracea
12
12
53
54
55
C19H15NO3
C20H17NO4
C19H17NO3
305
335
307
D. calycina
D. calycina
D. spixianaa
20
19
21,23
39
40
41
C20H21NO4
C19H21NO4
C20H23NO4
339
327
341
8-Nitroisocorydine
Calycinine
42
43
C20H22N2O6
C18H17NO4
386
311
N-Methylcalycinine
Duguevanine
44
45
C19H19NO4
C19H19NO5
325
341
N-Methylduguevanine
46
C20H21NO5
N-Formylnoraporphines
N-Formylputerine
N-Formylxylopine
N-Formylbuxifoline
N-Formylduguevanine
47
48
49
50
N-Nitrosonoraporphines
N-Nitrosoanonaine
N-Nitrosoxylopine
7-Alkyl-substituted-6a,7-dehydroaporphines
Duguenaine
Duguecalyne
Duguespixine
Alkaloids from the Genus Duguetia
355
Duguetia sp.
D. furfuracea
D. furfuracea
D. vallicola
D. furfuracea
D. calycina
D. flagellaris
D. obovata
D. obovata
D. obovata
D. flagellaris
D. obovata
Dicentrine
Norisocorydine
Isocorydine
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Table II (Continued)
Alkaloid type and name
MW
Species
Ref.(s)
56
57
58
C17H17NO3
C18H19NO3
C18H19NO3
283
297
297
N-oxypachyconfine
Oliveroline
59
60
C18H19NO4
C18H17NO3
313
295
N-Oxyoliveroline
Rurrebanidine
Rurrebanine
Guatterine
N-Oxyguatterine
N-Methylguatterine
Noroliveridine
Oliveridine
61
62
63
64
65
66
67
68
C18H17NO4
C18H19NO4
C19H21NO4
C19H19NO4
C18H17NO5
C20H22NO4
C17H15NO3
C19H19NO4
311
313
327
325
341
340
281
325
Roemerolidine
N-Oxyoliveridine
69
70
C18H17NO4
C19H19NO5
311
341
D. spixianaa
D. spixianab
D. confinis
D. spixianaa
D. spixianaa
D. confinis
D. flagellaris
D. vallicola
D. odorata
D. flagellaris
D. spixianab
D. spixainab
D. confinis
D.confinis
D. odorata
D. spixianaa,b
D. spixianaa,b
D. glabriuscula
D. flagellaris
D. vallicola
D. spixianab
D. spixianaa,b
21
24
37
21
21
37
29,30
27
14
29,30
24
24
37
37
14
21,24
21,24
33
29,30
27
24
21,24
Edwin G. Pérez and Bruce K. Cassels
Molecular formula
7-Hydroxyaporphines
Norpachyconfine
Nornuciferidine
Pachyconfine
Structure
Author’s personal copy
21,24
21
21
21
33
36
29,30
11
11
309
337
D.
D.
D.
D.
D.
39,47
38
29,30
39
38
C18H17NO4
C19H19NO4
311
235
D. staudtii
D. staudtii
39
39
83
C17H9NO3
275
84
85
C18H13NO3
C19H15NO4
291
321
D.
D.
D.
D.
D.
10
39,40
24
24
15
71
72
73
74
75
76
C18H17NO4
C18H17NO5
C19H19NO5
C19H19NO6
C20H21NO5
C20H21NO5
311
327
341
357
355
355
N-Oxyduguetine
77
C20H21NO6
371
78
C18H17NO3
295
N-Methylpachypodanthine
N-Acetylpachypodanthine
79
80
C19H19NO3
C20H19NO4
7-Methoxy-4-hydroxyaporphines
Norpachystaudine
Pachystaudine
81
82
Oxoaporphines
Liriodenine
7-Methoxyaporphines
Pachypodanthine
Lysicamine
O-Methylmoschatoline
staudtii
confinis
flagellaris
staudtii
confinis
furfuracea
staudtii
spixianab
spixianab
stelechantha
Alkaloids from the Genus Duguetia
D. spixianaa,b
D. spixianaa
D. spixianaa
D. spixianaa
D. glabriuscula
Duguetia sp.
D. flagellaris
D. furfuracea
D. furfuracea
Duguexine
N-Oxyduguexine
Spixianine
N-Oxyspixianine
Polyalthine
Duguetine
99
Author’s personal copy
100
Table II (Continued)
Alkaloid type and name
Structure
Molecular formula
MW
86
87
C18H11NO4
C18H11NO4
305
305
Oxopukateine
88
C17H9NO4
291
Oxoputerine
89
C18H11NO4
305
Oxobuxifoline
90
C19H13NO5
335
Dicentrinone
Duguevalline
91
92
C19H13NO5
C20H15NO6
335
365
93
94
C19H21NO2
C20H23NO2
295
309
95
96
C22H23NO3
C21H25NO3
325
339
Aminoethylphenanthrenes
(6,6a-Secoaporphines)
Noratherosperminine
Atherosperminine
N-Oxyatherosperminine
Methoxyatherosperminine
Ref.(s)
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
D.
eximia
vallicola
colombiana
furfuracea
glabriuscula
furfuracea
spixianaa,b
eximia
stelechantha
eximia
calycina
obovata
glabriuscula
furfuracea
vallicola
28
27
31
10
33
10
21,24
28
15
28
17
20
33
11
27
D.
D.
D.
D.
D.
calycina
spixianaa
calycina
spixianaa
spixianaa
18
21
17
21
21
Edwin G. Pérez and Bruce K. Cassels
Atherospermidine
Lanuginosine
Species
Author’s personal copy
97
98
C15H8N2O
C16H10N2O2
232
246
D. hadrantha
D. hadrantha
16
16
1-Aza-4,5-dioxoaporphines
Hadranthine A
Hadranthine B
Imbiline-1
99
100
101
C18H14N2O4
C16H10N2O3
C17H12N2O3
322
278
292
D. hadrantha
D. hadrantha
D. hadrantha
16
16
16
Azahomoaporphines
Spiguetine
Spiguetidine
102
103
C18H16N2O3
C19H18N2O3
308
322
D. spixianab
D. spixianab
24
24
Azaanthraquinone
Cleistopholine
104
C14H9NO2
223
D. vallicola
27
Protoberberine styrene adduct
Staudine
105
C31H33NO7
531
D. staudtii
39,48
D. spixiana from Colombia.
D. spixiana from Bolivia.
b
Alkaloids from the Genus Duguetia
a
Copyrine alkaloids
1-Aza-7-oxoaporphines
Sampangine
3-Methoxysampangine
101
Author’s personal copy
102
Table III Alphabetical list of alkaloids isolated from the genus Duguetia with their synonyms and structure numbers
Name
Structure Name
Dehydrodiscretine
( )-10-Demethylxylopinine
Dicentrine
(N,O-Dimethylactinodaphnine, Eximine)
Dicentrinone
( )-Discretamine
( )-Discretine
Duguecalyne
Duguenaine
Duguespixine
Duguetine
Duguevalline
16
11
39
Imbiline-1
Isoboldine (N-Methyllaurelliptine)
Isochondodendrine
Isocorydine (Artabotrine, Luteanine)
( )-Isocorypalmine
Isolaureline (N-Methylxylopine)
Isopiline
Jatrorrhizine
Lanuginosine (Oxoxylopine)
Liriodenine (Oxoushinsunine,
Micheline B, Spermatheridine)
Lysicamine (Oxonuciferine)
Methoxyatherosperminine
3-Methoxysampangine
91
4
10
54
53
55
76
92
N-Methylasimilobine
N-Methylbuxifoline
N-Methylcalycinine
N-Methylduguevanine
N-Methylglaucine
N-Methylguatterine
O-Methylisopiline (O-Methylnorlirinine)
N-Methyllaurotetanine (Lauroscholtzine, Rogersine)
101
38
3
41
6
29
24
15
87
83
84
96
98
21
34
44
46
36
66
26
37
Edwin G. Pérez and Bruce K. Cassels
N-Acetylpachypodanthine
80
Anolobine
27
Anonaine
23
Asimilobine
20
Atherospermidine (Psilopine)
86
Atherosperminine
94
Buxifoline
33
Calycinine
43
Cleistopholine
104
( )-Corypalmine (Tetrahydrojatrorrhizine)
5
Structure
Author’s personal copy
O-Methylmoschatoline (Liridine, Homomoschatoline) 85
N-Methylpachypodanthine
79
O-Methylpukateine
32
N-Methyltetrahydropalmatine
8
8-Nitroisocorydine
42
N-Nitrosoanonaine
51
N-Nitrosoxylopine
52
Noratherosperminine
93
Norglaucine
35
Norisocorydine
40
Nornuciferidine
57
Nornuciferine
22
Pachystaudine
82
Polyalthine
75
Pseudopalmatine
17
Puterine
31
(þ)-Reticuline
1
Roemerolidine
69
Rurrebanidine
62
Rurrebanine
63
Sampangine
97
(9S)-Sebiferine
18
( )-Spiduxine
13
Spiguetidine
103
Spiguetine
102
Spixianine
73
103
45
71
49
50
47
48
10
9
64
99
100
25
67
56
81
30
68
60
90
88
89
95
2
77
72
65
Alkaloids from the Genus Duguetia
Duguevanine
Duguexine
N-Formylbuxifoline
N-Formylduguevanine
N-Formylputerine
N-Formylxylopine
( )-Glaziovine
( )-Govanine
Guatterine
Hadranthine A
Hadranthine B
3-Hydroxynornuciferine
Noroliveridine
Norpachyconfine
Norpachystaudine
Obovanine
Oliveridine
Oliveroline
Oxobuxifoline
Oxopukateine
Oxoputerine
N-Oxyatherosperminine
cis-N-Oxycodamine
N-Oxyduguetine
N-Oxyduguexine
N-Oxyguatterine
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104
Table III (Continued)
Name
70
61
59
74
58
78
Staudine
( )-Tetrahydropalmatine (Rotundine)
( )-Thaicanine
Xylopine (O-Methylanolobine)
( )-Xylopinine
Structure
105
7
14
28
12
Edwin G. Pérez and Bruce K. Cassels
N-Oxyoliveridine
N-Oxyoliveroline
N-Oxypachyconfine
N-Oxyspixianine
Pachyconfine
Pachypodanthine
Structure Name
Author’s personal copy
105
Alkaloids from the Genus Duguetia
and in other instances the structure elucidations were straightforward,
relying largely on the NMR spectra of the alkaloids. For this reason, in
this section only the more problematic structure assignments will be
discussed.
Benzylisoquinoline type
Berbine type
Bisbenzylisoquinoline type
Isochondodendrine subtype
N
CH3
8´
12 O
R
Protoberberine type
N
R´
1´
N
8 O
1
12´
N
Morphinandienone type
Proaporphine type
N
N
R
N R
O
O
Aporphine type
Aporphine sensu
stricto subtype
N-Formylnoraporphine
subtype
N-Nitrosonoraporphine
subtype
4
5
2
N
1
N
CH3
O
N
N
O
H
7
10
9
Duguenaine subtype
N
Duguespixine subtype
N
O
7-Hydroxyaporphine subtype
H
O
CH3
Figure 1 Structural types of alkaloids isolated from Duguetia species.
N
R
OH
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Edwin G. Pérez and Bruce K. Cassels
7-Oxoporphine subtype
Aminoethylphenanthrene subtype
R
R
N
N
O
COPYRINE ALKALOIDS
1-Aza-7-oxoaporphine subtype
1-Aza-4,5-dioxoaporphine subtype
O
O
N
N
N
N
R
O
Azahomoaporphine type
1-Azaanthraquinone type
O
N
CH3
CH3
N
N
O
Figure 1
(Continued)
A. Benzyltetrahydroisoquinolines
Only two, unelaborated, benzyltetrahydroisoquinolines have been
reported from the genus Duguetia, namely, reticuline (1), isolated from
Duguetia trunciflora and D. furfuracea (10,35), and cis-N-oxycodamine (2),
isolated from Duguetia spixiana (21,22).
5
H3CO 6
4
3
N2
1 CH3
7
HO
HO
2´
4´
H3CO
H3CO
N
HO
H3CO
6´
H3CO
1
2
O
CH3
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Alkaloids from the Genus Duguetia
107
B. Bisbenzyltetrahydroisoquinolines
The head-to-tail/head-to-tail dimer isochondodendrine (3), isolated from
D. furfuracea (10), is the only bisbenzyltetrahydroisoquinoline recorded to
date from this genus.
H3CO
N
HO
CH3
O
H3C
O
N
OH
OCH3
3
C. Berbines and Protoberberines
The berbines or tetrahydroprotoberberines appear to be widely distributed in the genus Duguetia (10 out of 15 16 species studied).
Although quantitative analyses are lacking, it is noteworthy that these
alkaloids comprise more than 50% of the mass of alkaloids isolated from
the bark of the African D. confinis, and about 20% of D. staudtii, while
they are apparently less abundant in the New World species. It is also
noteworthy that, aside from their common precursor reticuline (1), the
other five alkaloids isolated from D. trunciflora are members of this
structural type, as do all three Duguetia gardneriana alkaloids. With the
exception of spiduxine (13, only known so far from D. spixiana) and
thaicanine (14, from D. trunciflora, but isolated previously from other,
non-Annonaceous species), their structures are quite commonplace.
A single paper on the constituents of D. trunciflora reported the
presence of reticuline (1), the berbines tetrahydropalmatine (THP)
(rotundine) (7), tetrahydrojatrorrhizine (corypalmine) (5), discretamine
(4), and thaicanine (14), and the protoberberine jatrorrhizine (15) (29).
Although the optical rotations of the chiral members of this series were
not published, all four berbines can be expected to have the usual
S-configuration, and the same is true for the reticuline (1) isolated from
this plant, if it is the biosynthetic precursor of the other isolates, and not,
in this case, a dead-end metabolite with the R stereochemistry.
A report on the hypotensive and vasorelaxant effects of discretamine
(4) from Duguetia magnolioidea Maas (34) refers to experimental details of
the isolation ‘‘according to the method described by Fechine et al. (2002)’’
(35). Unfortunately, the report provides no information as to the location
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108
Edwin G. Pérez and Bruce K. Cassels
where the plant was collected, its identification, or the existence of a
voucher specimen.
In this genus, the quaternary N-methyltetrahydropalmatine (8)
has only been isolated from D. furfuracea. Although its putative
precursor, THP (also named rotundine, 7) has not been reported
from this species, its 3,10-dihydroxy analog discretamine (4) is present
in D. furfuracea, D. calycina, D. gardneriana, D. magnolioidea, and
D. trunciflora (10,17,32,34,35).
R3O
R2O
N
H3CO
3
H3CO
2
N
CH3
OCH3
OR10
11
4 : R2 = CH3, R3= R10 = H
5 : R2 = R10 = CH3, R3= H
6 : R2 = H, R3= R10 = CH3
7 : R2 = R3= R10 = CH3
9
OCH3
10
OCH3
8
R3O
R2O
N
OR10
OCH3
9 : R2 = H, R3=R10 = CH3
10 : R2 = R10 = CH3, R3= H
11 : R2 = R3= CH3, R10 = H
12 : R2 = R3= R10 = CH3
Protoberberines, easily formed nonenzymatically on prolonged
exposure of berbines to air, have been isolated less often from Duguetia,
but the co-occurrence of jatrorrhizine (15) and its tetrahydro analog
corypalmine (5¼tetrahydrojatrorrhizine) in D. trunciflora, and of pseudopalmatine (17) and the corresponding xylopinine (12) in Duguetia
vallicola suggest that at least in these species they might be artifacts of
storage or isolation. Thaicanine (14) is presumably a hydroxylation
metabolite of THP (7). The C12-formylated spiduxine (13) from
Author’s personal copy
Alkaloids from the Genus Duguetia
109
Colombian D. spixiana is viewed as a (tetrahydro)retroprotoberberine
(see Section V).
R3O
HO
N
H3CO
H3CO
N
OCH3
OCH3
OCH3
16 : R3 = H
17 : R3 = CH3
OCH3
15
D. Morphinandienone
(9S)-Sebiferine (18) is the only morphinandienone reported from this
genus, as a constituent of Duguetia obovata (20).
OCH3
H3CO
N CH3
H3CO
O
18
E. Aporphinoids
1. Proaporphines
Proaporphines, like the morphinandienones, seem to be uncommon in
Duguetia. Only glaziovine (19) has been reported from the leaves of
D. vallicola in which it is quite abundant (26).
H3CO
N
HO
O
19
CH3
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Edwin G. Pérez and Bruce K. Cassels
2. Aporphines sensu stricto
Aporphinoids in general are richly represented in the genus
Duguetia. Aporphines sensu stricto 43 46, N-formylduguevanine (50),
the 7-hydroxyaporphines (73 74), and the oxoaporphine duguevalline
(92), present the unusual 9,11-dioxygenation pattern.
OR3
2
RO
H3CO
O
N
H3CO
R6
NH
O
20 : R 2 = R6 = H
21 : R2 = H, R6 = CH3
22 : R 2 = R6 = CH3
NH
R1O
24 : R 1 = H, R3 = CH3
25 : R 1 = CH3, R3 = H
26 : R 1 = R3 = CH3
23
OCH3
O
O
N
O
R6
O
N
O
R6
N
O
R6
11
R O
OR9
OCH3
27 : R6 = R9 = H
28 : R6 = H, R9 = CH3
29 : R6 = R9 = CH3
H3CO
30 : R6 = R11 = H
31 : R6 = H, R11 = H
32 : R6 = H, R11 = CH3
H3CO
NH
H3CO
H3CO
H3CO
CH3
N
CH3
H3CO
H3CO
OCH3
35
33 : R6 = H,
34 : R6 = CH3
N
R1O
R6
H3CO
OCH3
36
OR9
37 : R 1 = R6 = CH3, R9 = H
38 : R 1 = R9 = H, R6 = CH3
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Alkaloids from the Genus Duguetia
H3CO
O
N
O
H3CO
HO
CH3
H3CO
N
R6
H3CO
H3CO
N
H3CO
HO
H3CO
CH3
NO2
OCH3
40 : R 6 = H
41 : R 6 = CH3
39
42
OCH3
O
O
N
O
R6
N
O
HO
R6
HO
OCH3
OCH3
6
45 : R 6 = H
46 : R 6 = CH3
43 : R = H
44 : R 6 = CH3
3. N-Formylaporphines
Four N-formylaporphines have been reported from the genus Duguetia,
namely, N-formylputerine (47) from D. calycina (19), and N-formylxylopine (48), N-formylbuxifoline (49), and N-formylduguevanine (50) from
D. obovata (20).
O
O
N
O
H3CO
C
H
O
N
O
C
H
O
OCH3
47
48
OCH3
OCH3
O
O
N
O
C
H
O
N
O
HO
OCH3
OCH3
49
50
C
H
O
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Edwin G. Pérez and Bruce K. Cassels
4. N-Nitrosoaporphines
Two N-nitrosonoraporphines, N-nitrosoanonaine (51) and N-nitrosoxylopine (52) have been reported from D. furfuracea. The structure of
N-nitrosoanonaine (51) was confirmed by X-ray crystallography (12). The
same authors have very recently reported the presence of 8-nitroisocorydine (42) in the same plant (13).
O
O
N
O
N
O
N
O
N
O
OCH3
51
52
5. 7-Alkyl-6a,7-didehydroaporphines
Duguenaine (53) and duguecalyne (54) were isolated from D. calycina
(19,20), and duguespixine (55) from the bark of the Colombian D. spixiana
(21,23). The latter alkaloid was also found in Guatteria sagotiana (49), but
to date duguecalyne (54) and duguenaine (53) seem to be exclusively
Duguetia metabolites.
O
HO
O
N
O
O
53
N
O
H3CO
N
H3CO
O
CH3
O
54
H
55
6. 7-Hydroxyaporphines
The genus Duguetia is remarkably rich in 7-hydroxylated aporphines, of
which a small number have also been isolated from Guatteria species.
Although only found in one half of the species studied, they account for
nearly two thirds of the mass of alkaloids isolated from both Colombian
and Bolivian D. spixiana.
Author’s personal copy
Alkaloids from the Genus Duguetia
O
O
O
N
CH3
H
OH
O
113
O
N
CH3
H
OH
O
HO
O
N
CH3
H
OH
O
HO
OCH3
71
70
72
OCH3
O
O
O
N
CH3
H
OH
O
HO
O
N
CH3
H
OH
O
HO
N
CH3
H
OH
O
OCH3
OCH3
OCH3
73
74
75
O
O
N
CH3
H
OH
O
H3CO
O
N
CH3
H
OH
O
H3CO
OCH3
OCH3
76
77
The closely related pachypodanthine (78), N-methylpachypodanthine
(79), N-acetylpachypodanthine (80), pachystaudine (82), and norpachystaudine (81), all C7 methoxylated, are characteristic of the African
species D. staudtii and D. confinis (formerly designated as Pachypodanthium). Although a few other C4 C7 oxygenated aporphines (e.g.,
stephadiolamine) and oxoaporphines are known, pachystaudine (82) and
its nor-analog 81 seem to be the only aporphinoids characterized to date
with both C4 hydroxy and C7 methoxy substituents.
OH
O
O
O
N 6
R
H
OCH3
78: R 6 = H
79: R 6 = CH3
80: R 6 = COCH3
O
N 6
R
H
OCH3
81: R 6 = H
82: R 6 = CH3
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Edwin G. Pérez and Bruce K. Cassels
7. Oxoaporphines
Nine 7-oxoaporphine alkaloids (7-oxo-4,5,6,6a-tetradehydroaporphines)
have been isolated from Duguetia species, scattered throughout the
genus. Perhaps significantly, all three alkaloids identified as constituents
of Duguetia eximia belong in this group (28).
So far, duguevalline (92) is only the second oxoaporphine known to
have the unusual 9,11-dioxygenation pattern. The other, oxoisocalycinine, was isolated from Guatteria discolor (50).
OCH3
H3CO
H3CO
O
N
O
N
H3CO
O
O
85
O
O
O
N
O
O
84
83
OCH3
N
H3CO
N
O
O
N
O
R11O
O
O
OCH3
86
88 : R 11 = H
89 : R 11 = CH3
87
OCH3
OCH3
OCH3
O
O
N
O
O
N
O
O
O
N
O
H3CO
O
H3CO
OCH3
OCH3
90
91
OCH3
92
F. Miscellaneous Aporphinoid- and Berbinoid-Related Alkaloids
1. Aminoethylphenanthrenes
Four 1-aminoethylphenanthrenes, or 6,6a-secoaporphines, have been
isolated from Duguetia species, these are: atherosperminine (94, from
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Alkaloids from the Genus Duguetia
115
D. spixiana and D. calycina), its N-oxide (95, from D. spixiana),
noratherosperminine (93, from D. calycina), and methoxyatherosperminine (96, from D. spixiana).
R6
N
H3CO
CH3
H3CO
OCH3
CH3
N O
CH3
H3CO
H3CO
H3CO
H3CO
93 : R6 = H
94 :R6 = CH3
CH3
N
CH3
95
96
2. Copyrine Alkaloids
The relatively rare 1-azaaporphinoids are often referred to as
copyrine alkaloids, by analogy with the term isoquinoline alkaloids,
as copyrine is the trivial name of the 2,7-diazanaphthalene nucleus.
Three 1-aza-4,5-dioxo-7-methoxy-6a,7-didehydroaporphines and two
1-aza-7-oxo-4,5,6,6a-tetradehydroaporphines were isolated from
Duguetia hadrantha (16). The fact that these five unusual compounds
are the only alkaloids isolated from this particular species, and that
they have been found in no other Duguetia species, is probably a
consequence of the antimalarial/antifungal bioassay-guided fractionation of the plant extract. They are biogenetically related to
cleistopholine (104), which in this genus has only been recorded as
a constituent in D. vallicola, and to other annonaceous 1-azaanthra9,10-quinone derivatives with scattered occurrence in the genera
Annona, Cleistopholis, Guatteria, Meiogyne, Porcelia, Hornschuchia, and
Cananga (51 56).
R3
O
O
N
N
N
N
R6
OCH3
O
R10
97 : R3 = H
98 : R3 = OCH3
99 : R6 = CH3, R10 = OCH3
100 : R6 = R10 = H
101 : R6 = CH3, R10 = H
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Edwin G. Pérez and Bruce K. Cassels
3. Azahomoaporphines
The only two azahomoaporphines found in the genus Duguetia are
spiguetine (102) and spiguetidine (103), reported exclusively from a
Bolivian accession of D. spixiana. They were not isolated from plant
material collected in Colombia (24). They are members of a rare alkaloid
structural type found only in this species, in G. sagotiana (dragabine),
and in Meiogyne virgata (nordragabine), all in the family Annonaceae.
O
N
O
N
CH3
R
102 : R = OCH3
103 : R = OH
4. Azaanthraquinone
Cleistopholine (104), the prototype of the few natural 1-aza-9,10anthracenedione alkaloids known to date, was isolated from D. vallicola
(27), and has also been found in several other Annonaceous genera.
O
CH3
N
O
104
5. Protoberberine Styrene Adduct
The structurally unique staudine (105) has only been isolated from
D. staudtii (39,48).
O
OCH3
N
H3CO
OCH3
H3CO
OCH3
OCH3
105
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IV. STRUCTURE AND CHEMISTRY
A. Benzyltetrahydroisoquinolines
Although the configuration of the reticuline (1) isolated from
D. trunciflora was not reported, it seems likely that it is the S isomer, as
in D. furfuracea, and therefore is the immediate precursor of (S)-codamine
and its N-oxide (2). The small amount of 2 isolated did not allow its
absolute configuration to be determined, but it is depicted here as the
more likely (S)-reticuline-derived S isomer (although in the original
reference it is shown with the R configuration). The berbines and the
1,2,9,10- and 1,2,10,11-dioxygenated aporphines, of which there are a few
in the source plant of cis-N-oxycodamine, the Colombian accession of
D. spixiana, are generally derived from (S)-reticuline (1).
B. Bisbenzyltetrahydroisoquinoline
The complete assignments of the 1H NMR and
isochondodendrine (3) have been published (10).
13
C NMR spectra of
C. Berbinoids
Quite surprisingly, the presence of (R)-dicentrine (39) and its 7-hydroxy
derivative duguetine (76) was reported in an unidentified Duguetia
species (36). This configuration flies in the face of biogenetic theory, but
seems to be supported by the negative optical rotation of both alkaloids
at 589 nm, and the ORD spectrum of the latter alkaloid. Unfortunately,
the only recent report on the reisolation of duguetine from Duguetia
flagellaris gives no details of its identification or of its physical (including
optical rotation) and spectral properties (29,30).
D. Morphinandienone
The stereochemistry of (9S)-sebiferine (18), which is opposite to that of
the morphine alkaloids of Papaver species, was demonstrated on the basis
of the crystal structure determination of its methiodide (57). Both (9S)sebiferine (18) and its enantiomer have been synthesized via p-quinol
esters starting from the diastereomeric products of the lead tetraacetate
oxidation of racemic N-trifluoroacetylnorcodamine in (S)-2-phenylpropionic acid (58) (Scheme 1).
E. Aporphinoids
The N-nitroso, non-phenolic noraporphines 51 and 52 were isolated from
a 95% ethanolic extract of the leaves of D. furfuracea which was treated
with 3% HCl. The authors appropriately state that N-nitrosamines can be
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Edwin G. Pérez and Bruce K. Cassels
OCH3
H3CO
HO
N
TFA
H3CO
a
OCH3
OCH3
H3CO
H3CO
H
TFA
N
O
H3CO
O
O
+
H
H3CO
O
H
O
N
TFA
O
H
separation
b, c, d
b, c, d
OCH3
OCH3
H3CO
H3CO
H
N CH3
+
H
N CH3
H3CO
H3CO
O
O
Scheme 1 Reagents and conditions: a. Pb(OAc)4, (S)-2-phenylpropionic acid; b. TFA,
CH3CN, 301C; c. N-deprotection; d. N-methylation.
carcinogenic and/or mutagenic (59), and also remark that they ‘‘can be
regarded as potential NO/NOþ donors, thus playing an important role
in the regulation of many physiological functions’’ (60). However, they
do not address the possibility that these N-nitroso-alkaloids are artifacts
of the isolation process.
Nitrates and nitrites commonly accumulate in higher plants. Their
occurrence in dietary vegetables has been viewed since at least 1964 as a
health hazard (61), and has been the subject of numerous subsequent
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119
publications. Moreover, treatment of some secondary amine alkaloids
with nitric acid has been known to lead to the formation of N-nitroso
derivatives since the end of the 19th century (62), and the N-nitrosation
of secondary amines occurs readily with inorganic nitrites and acid.
It therefore seems possible that the N-nitrosoanonaine (51) and
N-nitrosoxylopine (52) isolated by Carollo et al. were formed on
acidification of the ethanol extract of the plant. What concentration of
nitrate or nitrite was present in the Duguetia sample studied by these
authors is a question that would seem to be worth addressing.
In the opinion of the authors, nitration of isocorydine at the free C8
position, para to a phenol function to give 8-nitroisocorydine (42), should
occur under very mild conditions. This reinforces the hypothesis that
these unusual alkaloids are formed either in the living plant or during
the extraction procedure by (presumably nonenzymatic) reaction with
nitrates or nitrites present in the plant material. The 8-nitroisocorydine
structure, however, does not seem to have been established unambiguously. The N-methyl 1H resonance is not reported (its 13C resonates at the
normal chemical shift value of 43.9 ppm), and the mass-spectral
fragmentation shows a possibly suspicious loss of NO from the
molecular ion. Is it possible that this isolate is 8-nitrosoisocorydine
N-oxide, with one or two apparently anomalous N-methyl resonances as
described by Debourges et al. (22). It is probably important to remember
that D. furfuracea is one of the three Duguetia species known to
accumulate at least one aporphine N-oxide (11).
A biomimetic synthesis of the unusual oxazine-condensed aporphine
duguenaine (53) and some related analogs has been reported, based on the
UV irradiation of an ethanol-tetrahydrofuran solution of 1-benzylidene6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-2-ethoxycarboxylate in
the presence of iodine to produce N-ethoxycarbonyldehydro-anonaine.
This was followed by N-deprotection under basic conditions and
quenching with aqueous citric acid to yield the dehydroanonaine salt. The
oxazine ring was introduced by treating dehydroanonaine with aqueous
formaldehyde at room temperature for 24 h (Scheme 2) (63).
An alternative synthesis of duguenaine (53) was published almost
simultaneously, using anonaine (23) as the starting material. Anonaine
was treated with N-chlorosuccinimide yielding the corresponding
N-chloroanonaine. Sodium ethoxide was added to the mixture and the
resulting dehydroanonaine was treated with aqueous formaldehyde
under reflux for 30 min to furnish 53 (Scheme 3) (23).
F. Miscellaneous Aporphinoid- and Berbinoid-Related Alkaloids
Imbiline 1 (101) has been synthesized fairly recently, in seven steps,
starting from 4-methoxy-1-naphthylamine, in 9% overall yield (64).
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Edwin G. Pérez and Bruce K. Cassels
O
O
NCO2Et
O
a
NCO2Et
O
b
O
O
N
O
NH
O
O
c
53
Scheme 2 Reagents and conditions: a. UV, EtOH-THF, I2, 9.5 h; b. KOH, EtOH, reflux
18 h; c. HCHO, dioxane, rt, 24 h.
O
O
N
O
H
a
N
O
23
Cl
b
O
O
N
O
c
O
N
O
53
Scheme 3
Reagents and conditions: a. NCS; b. NaOEt; c. HCHO, reflux 0.5 h.
Staudine (105, relative configuration shown), isolated from D. staudtii, is
a unique reverse electron demand Diels Alder adduct of jatrorrhizine
(15) and 2,4,5-trimethoxystyrene, which is an abundant metabolite in this
plant. Its zwitterionic, rather than phenolic, character, suggested by its
high melting point (205 2061C), was revealed by the absence of any
change in its UV-VIS spectrum in alkaline solution, and by the failure of
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121
an attempted acetylation with acetic anhydride in pyridine in the
presence of 4-dimethylaminopyridine. The presence of a C¼Nþ double
bond was apparent from its IR spectrum, which exhibited a strong band
at 1605 cm 1. This band disappeared on reduction of staudine (105) with
sodium borohydride in methanol to afford a dihydro derivative 106 that
undergoes facile reoxidation to staudine (105) in the presence of air.
The 1H NMR spectrum of staudine (105) showed the presence of six
methoxy groups, two single proton multiplets at d 4.45 and 5.17, and five
aromatic proton singlets (one due to two protons, the others to one each).
One of the methoxyl resonances (at 3.37 ppm) and one of the aromatic
proton signals (at 5.32 ppm) exhibited unusual deshieldings which could
be attributed to a structure with closely superimposed aromatic rings.
The mass spectrum showed a weak (1%) molecular ion peak, and more
abundant fragments at m/zo360. Of particular interest were three peaks
at m/z 194 (90%), 179 (40%), and 151 (37%), corresponding to a
trimethoxystyrene. The base peak occurred at m/z 337 (Mþ-194) with
another strong signal at m/z 352 (30%, Mþ-179). These data suggested
that staudine (105) contains a benzylisoquinoline moiety in addition to
the trimethoxystyrene moiety, which seem to undergo a retroDiels Alder reaction in the mass spectrometer. The 13C NMR spectrum
showed all the signals expected for 2,4,5-trimethoxystyrene, with the
exception of the ethylene carbon resonances, and all the signals expected
for corypalmine (tetrahydrojatrorrhizine, 5), except for the C14 resonance, plus additional resonances at 32.8, 34.0, and 176.3 ppm. All these
data, and further tentative assignments of the sp3 13C resonances,
showed that the structure of staudine (105) incorporates a 2,4,5trimethoxystyrene moiety bonded through its vinyl side chain to C8
and C13 of corypalmine, but with a C14N double bond. This was
confirmed by the pyrolysis of staudine (105) under high vacuum at
1801C, which led to the sublimation of 2,4,5-trimethoxystyrene, leaving a
highly polar residue. Sodium borohydride reduction of this residue
afforded the previously characterized dihydrostaudine (106) and
corypalmine (5) (Scheme 4).
Definitive proof of the structure was provided by an X-ray crystallographic analysis, which showed unambiguously that the benzylic
carbon of the styrene residue is bonded to C13 of the corypalmine moiety,
and that the more distal styrene carbon atom is bonded to C8. Heating
jatrorrhizine (15) and 2,4,5-trimethoxystyrene in bromobenzene at 1001C
for 10 h produced only a small amount of staudine (105), identified by
TLC, leading the authors to conclude that this alkaloid is not an isolation
artifact (48). Nevertheless, this conclusion is still arguable considering
that the same authors reported an [a]D¼0 for this alkaloid with three
stereogenic carbon atoms and, as the crystal structure shows, a highly
dissymmetric arrangement of the three benzene chromophores which
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Edwin G. Pérez and Bruce K. Cassels
O
HO
OCH3
N
H3CO
OCH3
N
H3CO
OCH3
OCH3
a
b
H3CO
H3CO
OCH3
OCH3
OCH3
OCH3
105
106
c
HO
d
N
H3CO
OCH3
HO
N
H3CO
OCH3
OCH3
15
5
OCH3
+
OCH3
H3CO
OCH3
Scheme 4 Conditions: a. NaBH4, MeOH; b. Air; c. 1801C, 0.01 Torr, 6 h; d. KBH4, MeOH.
could be expected to result in a fairly high optical rotation. The crystal
packing was not reported and it is therefore not possible to determine if
the eight molecules in the unit cell have the same configuration, or if the
crystal itself is racemic.
It may be pointed out that 2,4,5-trimethoxystyrene, which is quite
toxic to brine shrimp, but only weakly cytotoxic, has been reported as the
major bioactive constituent of Duguetia panamensis Standley (no studies
have been published on the alkaloids of this species) (65), and is also
present in Duguetia colombiana (31).
V. BIOSYNTHESIS, BIOGENESIS, AND CHEMOSYSTEMATICS
No biosynthetic work has been conducted specifically on plants belonging to
the Annonaceae. However, earlier studies of tetrahydrobenzylisoquinoline
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123
alkaloid biosynthesis can be generalized to the more widespread Duguetia
alkaloids. Regarding biogenetic speculations, some of which have been
summarized in an earlier chapter of this series (51), the situation is similar.
Some recent developments, both experimental and hypothetical, are
reviewed here.
(S)-Reticuline (1) and codamine cis-N-oxide or oxycodamine (2) lie
near the base of the biosynthetic branch leading to most of the Duguetia
alkaloids. As the 1,2,9,10- and 1,2,10,11-oxygenated aporphines and the
berbines are all derived from (S)-reticuline (1), but not codamine, the cisN-oxycodamine of D. furfuracea can be regarded as a terminal
biosynthetic product.
(S)-Reticuline (1) is the biosynthetic precursor of all known berbines
and the 9,10- and 10,11-dioxygenated aporphinoids, and, through the
unstable 1,2-dehydroreticuline, is also the precursor of (R)-reticuline, the
common precursor of most morphinandienone alkaloids. Reasoning
biogenetically, ( )-dicentrine (39) should originate by direct C8 C6u
coupling of (R)-reticuline. It is therefore of interest to note that 1,2dehydroreticuline synthase, the enzyme at the branching point that
separates (R)- and (S)-reticuline metabolites, has been partially purified
and shown to not require a redox cofactor, accepting both (S)-reticuline
and (S)-norreticuline as substrates (66).
The occurrence of isochondodendrine (3) as the sole Duguetia
bisbenzyltetrahydroisoquinoline parallels the limited occurrence of
benzyltetrahydroisoquinoline dimers in Guatteria. In the largest genus
in the Annonaceae, these alkaloids, although many in number, appear to
be restricted to G. boliviana, G. guianensis, and G. megalophylla (51,67).
Guatteria gaumeri, reported to contain a bisbenzylisoquinoline, is a
misnomer for Malmea gaumeri, now viewed as a synonym of Malmea
depressa (68). Moreover, cladistic analysis indicates that the split between
the branches leading to Malmea (the short branch clade of the
Annonaceae) and to Duguetia and Guatteria (the long-branch clade) must
have occurred about 60 million years ago, 20 million years before the
differentiation of the latter genera (46). Within the long-branch clade, the
only other genera for which bisbenzylisoquinolines have been recorded
are Isolona, Uvaria, and Xylopia. This suggests that the cytochrome P450
oxidases that presumably catalyze the intermolecular oxidative phenol
couplings (two in succession in the case of isochondodendrine) of two
coclaurine units (69) are poorly expressed in this group.
In the last few years, particularly important contributions have been
made to the knowledge of the berberine bridge enzyme. This protein,
incorporating a unique, bi-covalently attached FAD prosthetic group
(70), catalyzes the conversion of (S)-reticuline to (S)-scoulerine by
oxidation of the N-methyl group and coupling ortho to the phenol group
of the benzyl ring (71,72). A mechanism has been proposed involving the
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Edwin G. Pérez and Bruce K. Cassels
removal of hydride from the N-methyl group by the FAD cofactor, and
concerted carbon carbon coupling combined with base-catalyzed proton abstraction (73). The enzyme also oxidizes the berbine alkaloid
scoulerine to the protoberberine dehydroscoulerine, resembling (S)tetrahydroprotoberberine oxidase (STOX) and canadine oxidase in this
regard (74). (S)-Tetrahydroprotoberberine oxidase converts (S)-tetrahydrocolumbamine to columbamine in the metabolic pathway leading to
berberine, jatrorrhizine, and palmatine in Berberis species (75). Canadine
oxidase catalyzes an alternative route in which formation of the dioxole
ring precedes the dehydrogenation leading to berberine (76).
(S)-Reticuline (1) is not the exclusive berbine precursor. Berberine
bridge enzyme of Eschscholtzia californica, heterologously expressed in
insect cells, transforms other (S)- (but not R-configured) tetrahydrobenzylisoquinolines with a 2u-hydroxy group into (S)-berbines, apparently
regardless of the substitution pattern on the benzene ring of the
isoquinoline moiety of the precursor (77). In Corydalis and Macleaya cell
cultures both (S)-reticuline and (S)-protosinomenine (the isomer of
reticuline with the positions of the ring A hydroxy and methoxy groups
interchanged), but not their enantiomers, undergo the analogous
cyclization to (S)-scoulerine and tetrahydropalmatrubine (its methoxy
derivative at C2) (78). On the other hand, when racemic laudanine (the 7O-methyl ether of reticuline) was fed to the cells, both enantiomers of
scoulerine and of the 10,11-dioxygenated berbine corytenchine were
formed, in different enantiomeric ratios (78).
N-Methyltetrahydropalmatine (8) and the analogous N-methylstylopine and N-methylcanadine are synthesized in opium poppy from the
corresponding racemic berbines by a recently cloned and characterized
S-adenosyl-L-methionine:tetrahydroprotoberberine cis-N-methyltransferase (TNMT) which, however, does not modify (S)-scoulerine (79). The
stereochemistry of the products was not determined. TNMT activity was
detected in several other members of the Papaveraceae, but not in
representatives of the Berberidaceae, Menispermaceae, and Ranunculaceae. It remains to be seen if this, or some similar, enzyme is active in the
Annonaceae, and specifically in D. furfuracea.
It is worth pointing out that no 2-hydroxyberbines or protoberberines
have been found in Duguetia, although there are a number of occurrences
of 3-hydroxyberbines [discretamine (4), corypalmine (5), and discretine
(10)] and the oxidation products of 5 and 10 [jatrorrhizine (15) and
dehydrodiscretine (16)]. Assuming that all berbines are formed from (S)norreticuline by a berberine bridge enzyme (73,77,78), this would seem to
imply that the formal translocation of a methyl group from the methoxyl
at C2 to the C3 hydroxyl group is a practically universal occurrence in
this genus. In the rather well-studied genus Guatteria, coreximine (2,11dihydroxy-3,10-dimethoxyberbine, one of the putative precursors of the
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Alkaloids from the Genus Duguetia
whole series) is present in two out of four berbine-accumulating species
reviewed two decades ago (51). The fact that only 4 out of 18 Guatteria
species were shown to contain berbines (and protoberberines were not
recorded) suggests that the berberine bridge pathway is considerably less
active in Guatteria than in Duguetia. The presence of spiduxine (13) and
thaicanine (14) in Duguetia is another indication of the greater ability of
this genus to elaborate the berbine skeleton.
Regarding the (tetrahydro)retroprotoberberine spiduxine (13) (21),
Shamma proposed in his 1972 treatise on the isoquinoline alkaloids that
the related mecambridine, orientalidine, and their oxidation products
PO-5 and PO-4 might arise from a berbine by cleavage of the N C8 bond
giving a 1-benzyl-3,4-dihydroisoquinoline that could be reduced to its
tetrahydro counterpart, N-methylated, and a new ‘‘berberine bridge’’
built (80). This scheme is illustrated for the case of spiduxine (13)
(Scheme 5).
Elegant though this model may appear to be, it lacks experimental
support. Considering the ability of Duguetia species to introduce onecarbon units in the unexpected C7 position (viz. 53 55), for the sake of
parsimony one can also speculate that spiduxine is generated by
formylation ortho to the phenolic hydroxyl of 2-O-methylcoreximine.
Nevertheless, a few years ago the unusual structure of a new
benzyltetrahydroisoquinoline alkaloid named (þ)-argenaxine (106) (isolated from Argemone mexicana, Papaveraceae) was published (81), with a
H3CO
H3CO
N
H3CO
N
H3CO
OH
OCH3
OCH3
O
H3CO
OH
H3CO
N
H3CO
N
H3CO
CH3
OCH3
13
Scheme 5
O
OH
Proposed biogenesis of spiduxine.
OCH3
O
OH
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Edwin G. Pérez and Bruce K. Cassels
regio- and stereochemistry compatible with its hypothetical formation by
cleavage of an (S)-berbine and the possibility of it being a precursor of a
tetrahydroretroprotoberberine (or retroberbine).
O
NH
O
H
106
OCH3
OH OCH3
Interestingly, none of the berbines or protoberberines isolated from
Duguetia have a methylenedioxy group, suggesting that the enzyme that
effects closure of this ring in the many Duguetia methylenedioxyaporphinoids, supposedly a member of the CYP719A subfamily of
cytochrome P450s (82), does not accept the geometrically extended
berbine skeleton.
The apparently unusual stereochemistry of the morphinandienone
(9S)-sebiferine (18) seems to be justified by the fact that, at least in
Cocculus laurifolius (Menispermaceae), the biosynthetic conversion of (S)and (R)-reticuline (1) into sebiferine (18) is not stereospecific (83). The
C C phenolic coupling reaction of (R)-reticuline (1) to salutaridine is the
first morphinandienone-forming step, at least in morphine biosynthesis
(84), but the enzyme that catalyzes this reaction has not yet been
characterized.
Aporphines are believed to be formed by C C phenolic coupling
between C8 and C2u C6u of a benzylisoquinoline or, via an intermediate
proaporphine, between C8 and C1u. An enzyme catalyzing the first route,
CYP80G2, has now been cloned and characterized from Coptis japonica
(85). This enzyme converts (S)-reticuline (1) to its direct coupling product
(S)-corytuberine. If an analogous enzyme is operating in Duguetia, it
should be responsible for the formation of isocorydine (41), an
O-methylation product of corytuberine and the probably derived
norisocorydine (40) of D. vallicola and D. furfuracea. The presence of the
proaporphine glaziovine (19) in D. vallicola is somewhat surprising
considering that its likely biogenetic derivatives, (R)-aporphines with the
1-hydroxy-2-methoxy, or the 1,10-dihydroxy-2-methoxy, or 1-hydroxy2,10-dimethoxy substitution patterns seem to be completely absent from
the genus.
The 9,11-substitution pattern in the D ring of aporphines is of
taxonomic significance in the Annonaceae, as already noted by Roblot et
al. in 1983 (20). Only one aporphine with this structural feature has been
reported in the Ranunculaceae and Menispermaceae (86,87) and these
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127
alkaloids are mainly present in Guatteria and Duguetia (17,20,21,27,
29,30,50,88). In the review on Guatteria alkaloids published in this series
(51), it was proposed that one of the ring D substituents might be
introduced meta to the other, once the aporphine skeleton had been
generated from the appropriate proaporphine, stating that either the
C11-oxygenated puterine (31 in this review) or guadiscine (7,7-dimethyl9-methoxy-1,2-methylenedioxy-6,6a-didehydronoraporphine) could be
precursors of the 9,11-dioxygenated alkaloids, and that the process
might not be very regiospecific. Actually, guadiscine (present in
G. discolor and G. melosma) is only a reasonable precursor of guadiscoline
(7,7-dimethyl-9,11-dimethoxy-1,2-methylenedioxy-6,6a-didehydronoraporphine, only found in G. discolor), while 31 would be a possible
precursor of isocalycinine, discoguattine, oxoisocalycinine, guacolidine, and guacoline, all of which are Guatteria alkaloids, and are not
isolated from the genus Duguetia.
It is intriguing to note that the only American Duguetia species known
to accumulate a 7-methoxyaporphinoid [pachypodanthine (78), in the
abundant Amazonian D. flagellaris] should grow down to the coast of the
Brazilian states of Pará and Maranhão. This part of the South American
Gondwana fragment lies opposite to the western reaches of the Gulf of
Guinea and Sierra Leone, to which it was formerly attached, and where
D. staudtii now grows.
In the recent analysis of the anatomical and morphological data of
Duguetia and closely related genera (6), D. confinis and D. staudtii, earlier
described as Pachypodanthium, are placed close to the African species
Duguetia barteri (Benth.) Chatrou (also formerly Pachypodanthium) and
Duguetia dilabens Chatrou et Repetur (a new species) and to D. riberensis
of Venezuela, and presumably Colombia. It would be most interesting
if the latter plant could be collected and analyzed to determine if it
contains 7-methoxylated aporphinoids, like the reasonably well-studied
D. confinis and D. staudtii.
Pachystaudine (82) and norpachystaudine (81) are said, on the basis
of their CD spectra, to have the 6aS configuration. This stereochemistry is
exceptional for aporphinoids devoid of substituents on ring D, which are
generally believed to arise through the dienol benzene rearrangement of
proaporphines derived from (R)-coclaurine or norcoclaurine. This
apparent anomaly parallels the identification of the (R)-9,10-dioxygenated ( )-dicentrine (39), from the leaves of an unidentified Amazonian
species (36).
It was argued convincingly on the basis of their common 6aR
configuration (20), that the N-formylnoraporphines, found for the first
time in Duguetia species, cannot be metabolites of N-formyl-1-benzyltetrahydroisoquinolines originating from the cleavage of ring C of (14S)berbines as suggested earlier (89). In addition, it was indicated that the
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simultaneous presence of N-formyl-, N-methyl-, and noraporphines, and
the accumulation of the latter as major alkaloidal constituents in
D. calycina and D. obovata, pointed to the noraporphines as final
biogenetic products (20). Although the precise sequence was not
suggested, analogy with the catabolism of N-methyl groups in animals
allows the sequence aporphine
N-formylnoraporphine
noraporphine to be proposed. Noraporphines are therefore likely precursors of
the 7- and 4-hydroxynoraporphines, 7-oxo-, and 4,5-dioxoaporphines,
and finally the 1-azaaporphinoids (copyrine alkaloids), aristolactams,
azaanthraquinones, and their putative derivatives.
The isolated occurrence of duguevalline (92) in D. vallicola (27) and
oxoisocalycinine in G. discolor (50) as the only oxoaporphines with the
9,11-dioxygenation pattern is insufficient to suggest any chemosystematic trend. On the other hand, it might be significant that Colombian
D. spixiana accumulates seven N-oxides (five of them aporphine
N-oxides), while only one each are found in D. furfuracea, D. flagellaris,
and Bolivian D. spixiana, and only two in a single Guatteria species
(G. sagotiana) (51).
Aminoethylphenanthrenes or secoaporphines are thought to arise by
the Hofmann elimination of quaternary aporphine alkaloids (the
quaternization and elimination products are commonly termed
‘‘methines’’), and this indeed would seem to be the case for atherosperminine (94, nuciferine methine) and methoxyatherosperminine
(96, 3-methoxynuciferine methine). The formation of atherosperminine
N-oxide (95) appears to follow an important catabolic trend for
Colombian D. spixiana. Noratherosperminine (93) would presumably
arise through the N-demethylation of atherosperminine (94), probably
catalyzed by a cytochrome P450. An alternative explanation would
involve an anomalous Hofmann elimination reaction of the tertiary
nuciferine (necessarily in its N-protonated form?). Although such a
reaction has been documented in vitro for boldine (90) in refluxing
ammonium acetate solution, it seems extremely unlikely that it should
occur nonenzymatically in vivo. Therefore, one would have to assume the
existence of a ‘‘Hofmannase’’ for which there does not seem to be any
precedent.
It is interesting that only nuciferine and 3-methoxynuciferine are
involved in the biogenesis of these aminoethylphenanthrenes. Nornuciferine (22) and 3-hydroxynornuciferine (25) have been shown to
accumulate only in Bolivian D. spixiana, and the former also in
D. flagellaris, but their tertiary and quaternary analogs, the expected
precursors of their ring-opened products, have not been recorded for any
Duguetia species. This seems remarkable in view of the presence of the
close nuciferine congener anonaine (23) in Bolivian D. spixiana (and also
D. furfuracea), but not its N-methyl homolog roemerine, its quaternary
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derivative, or its seco counterpart. In all, 26 aporphines sensu stricto,
including several nor- and two quaternary aporphines, are listed
above, and only two of them can be envisioned as precursors of the
Duguetia aminoethylphenanthrenes. On the other hand, the quaternary
N-methylglaucine (36, from D. furfuracea) and N-methylguatterine
(66, from D. odorata) do not seem to undergo ring opening in this genus.
The phytochemical literature records a large number of aminoethylphenanthrenes, many from different Annonaceous genera, apparently
derived from aporphines with most of the various substitution patterns.
Therefore, the very limited occurrence of these alkaloids in Duguetia
suggests the hypothesis that they are the products of a metabolic route
involving a highly specific enzyme at some key step, possibly the
‘‘Hofmannase’’ mentioned above.
The copyrine alkaloids or 1-azaaporphinoids can be viewed as
aporphine derivatives in which ring A has been opened (e.g., by extradiol
cleavage of a 1,2-catecholic aporphine between C1 and C11b) with
subsequent reclosure through condensation with an ammonia molecule
(91). Taylor’s biogenetic proposal deriving the azafluoranthene, diazafluoranthene, tropoloisoquinoline, 1-azaanthracene, and azafluorenone
alkaloids from 1,2-dihydroxy-7-oxoaporphine (liriodendronine) through
an initial ring A cleavage (92,93) has been extended to explain the
formation of the hadranthines and imbilines via formal 1,4-hydrogenation
of the ketoimine function and stabilization by O-methylation, either
preceded, or followed by, conversion of pyridine ring B to the
b-ketolactam function (16). An alternative pathway to the 7-methoxylated
1-aza-4,5-dioxoaporphinoids or the 4,5-dioxocopyrines of D. hadrantha,
not requiring a reduction step, might start from N-methylliriodendronine,
in which the C7 oxygen function is already a phenoxy group, particularly
in view of the presence of many 7-hydroxy- and two 4-hydroxy-7methoxyaporphines in Duguetia (Scheme 6).
The proposal for the late oxygenation of C4 and C5 could be
circumvented by a parallel route to the 4,5-dioxocopyrines starting from
1,2-dihydroxy-4,5-dioxoaporphine, which leaves open the possibility of a
monooxygenase-catalysed hydroxylation at C7 (Scheme 7).
HO
O
HO
HO
+
NCH3
O-
O
COOH
+
NCH3
O
NCH3
OCH3
OCH3
Scheme 6 Initial steps of a proposed biogenetic pathway to 4,5-dioxocopyrines
starting from N-methylliriodendronine.
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HO
O
HO
HO
O
NH
COOH
O
O
O
NH
Scheme 7 First step of a proposed biogenetic pathway to 4,5-dioxocopyrines
starting from 1,2-dihydroxy-4,5-dioxoaporphine.
A biogenetic proposal to account for the formation of azahomoaporphines was published 20 years ago in this series (51). According to that
hypothesis, spiguetine (102) and spiguetidine (103) of the Bolivian
sample of D. spixiana might be derived from the 7-hydroxyaporphines
oliveridine (68) and roemerolidine (69), which are the major alkaloids of
the same plant.
It was suggested that a-aroylpyridine derivatives, and more
specifically 1-azaanthracene-9,10-diones, such as cleistopholine (104),
might undergo decarbonylation catalyzed by a metalloenzyme (93). This
has now received indirect support from the formation of metal
complexes of liriodenine (83) which confirm the metallophilicity of the
7-oxoaporphine arrangement of a pyridine nitrogen and a carbonyl
oxygen and, presumably, of related systems (94).
Some striking resemblances in the alkaloid chemistry of Duguetia
and Guatteria were pointed out by Cavé in 1984, as indicating the
possible proximity of these genera (95). At that time, it was known that
both Duguetia and Guatteria species accumulate 7-alkylated aporphinoids and N-formylnoraporphines. It was then suggested that the
unusual oxazine-condensed aporphine system of duguenaine (53) and
duguecalyne (54) might arise from ring closure of N-formyl-7methylaporphinoids or, alternatively, their 7-formyl-N-methyl counterparts, indicating that such potential intermediates had already been
found in D. spixiana (duguespixine, 55) and Guatteria trichostemon
(trichoguattine, the 1,2-methylenedioxy analog of 55). In fact, the related
9-hydroxylated belemine and goudotianine have also been isolated
from a couple of Guatteria species (96,97). Another common feature
pointed out by Cavé was the 9,11-dioxygenation pattern of some
Duguetia and Guatteria aporphinoids. At that time (1984), he noted that
the phenol function is located at C9 in Guatteria and at C11 in Duguetia.
This is not strictly so, as discoguattine, guacoline and guadiscoline are
9,11-dimethoxylated aporphinoids, but the first two alkaloids could
obviously be formed by O-methylation of their putative 9-hydroxy
precursors isocalycinine and guacolidine.
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It is worth mentioning that D. calycina and D. spixiana, the only
Duguetia species known to contain 1-aminoethylphenanthrenes, are
classed in the section Sphaerantha, and thus the occurrence of this
small group of alkaloids might be of chemosystematic significance.
Interestingly, atherosperminine, N-oxyatherosperminine, noratherosperminine, together with the 2-O-demethylated atherosperminine
analog argentinine (N-methylasimilobine methine), are the only
6,6a-secoaporphines isolated from the larger Annonaceous genus
Guatteria, and that from the single species G. discolor (50,98). However,
G. discolor appears to have arisen from fairly recent (Pliocene or
Pleistocene) diversification events within Guatteria (99), placing it at a
considerable evolutionary distance from the Eocene split that presumably originated Duguetia (46), and suggesting that aminoethylphenanthrene accumulation is not an ancestral character, but rather one that
has appeared in a scattered fashion in plants that synthesize aporphines,
either by convergent evolution or by cross-colonization by endophytic
fungi with the relevant synthetic abilities. As in Duguetia, the Guatteria
aminoethylphenanthrenes are formally and exclusively derived from
ring D-unsubstituted aporphines. As in the case of the copyrine
alkaloids, it has been proposed that the azahomoaporphine skeleton
arises by oxidative cleavage of the aporphine system, in this
case between C6a and C7, and reclosure incorporating an ammonia
molecule (100). Finally, if staudine (105) is in fact an enzymatic product,
one would have to invoke catalysis by a Diels Alderase to explain its
formation.
A striking aspect of the known alkaloid chemistry of Duguetia is
the apparent lack of correlation between the structures of the
isolated alkaloids and the morphologically based classification of
the genus into sections. Although the large section Duguetia, for
example, seems to be well-supported on morphological and genomic
grounds, none of the (relatively few) individual alkaloids isolated
from D. odorata and D. stelechantha have been found in the seemingly
exhaustive studies of D. furfuracea, classed in the same section. One
would like to find a more convincing degree of chemosystematic
order in such an extensively studied genus, but this will probably
be impossible without more exhaustive studies of some species,
and adequate quantification of the individual alkaloids in crude
extracts rather than the isolated yields, probably using a metabolomic (or metabonomic, or metabolic profiling) approach (101,102).
With a significantly more complete picture, it should become
possible to reasonably address the fascinating question of how
the diverging biosynthetic pathways present in Duguetia are
regulated.
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VI. ETHNOPHARMACOLOGY AND PHARMACOLOGY
Surprisingly little has been published on the ethnopharmacology of
Duguetia species, as recognized by the authors of one of the most recent
papers discussed here (13). A possible explanation is that most of these
plants grow in the Amazon region and, if they have medicinal or
related uses, are only employed by ethnic groups whose practices have
been poorly recorded by outsiders. As is the case with the bulk of
ethnopharmacological data, traditional uses are frequently difficult or
impossible to ascribe to medical conditions recognized by Western
science, and even less so to pharmacological mechanisms. Moreover, in
the vast majority of instances, the effectiveness of these practices has
not been substantiated scientifically through direct observation.
Furthermore, the literature reveals an unfortunate tendency to ascribe
a biological activity of a plant or a plant extract, obtained with little
regard to the traditional mode of preparation, to whatever can be
isolated (and often, but not always, biologically evaluated). Finally,
there is an almost complete absence of the quantitative analysis of the
active constituents, which can lead to the erroneous conclusion that a
substance present in insufficient amounts to produce any effect is
responsible in the field for test results obtained with the pure
compound.
D. furfuracea has two recorded uses in traditional medicine: its
powdered seeds are mixed with water and used to kill lice, and an
infusion of the twigs and leaves is used against rheumatism (13). D.
flagellaris is also used to treat rheumatism as an infusion in sugar cane
spirit (30,103). Duguetia glabriuscula is said to be used to kill cockroaches,
although the report does not mention what part of the plant is
insecticidal (104). The insecticidal uses of Duguetia species are probably
not related to their alkaloid content, but rather to the presence of the socalled ‘‘Annonaceous acetogenins,’’ characteristic of many Annonaceae,
but not yet reported for the genus Duguetia. It is worth noting that the use
of powdered Annonaceae seeds as insecticides was first recorded four
centuries ago (105).
D. confinis is used in tropical Africa as a cough suppressant and
analgesic, particularly for toothache (37). The stem bark of D. staudtii is
used by some populations in the Ivory Coast as an arrow poison
ingredient. The bark is also frequently used in traditional medicine for
several indications: ground to a pulp with kola nut it is used to treat
gastrointestinal pain and locally, mixed with Ficus exasperata leaves, as an
anti-inflammatory; it is also considered an analgesic, and some
populations in the Congo use it for cough, and for difficulty in breathing.
The Pomo tribe, also in the Congo, claims that the bark of this species is a
purgative and an aphrodisiac (39).
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No ethnopharmacological data seem to have been published for any
other Duguetia species. In contrast, although information is lacking
regarding the pharmacology of most individual Duguetia alkaloids, the
last two decades have seen an extraordinary number of papers on the
biological properties of a few alkaloids that are either abundant,
characteristic, or recognized as active principles of other plants, and are
also present in Duguetia. Additionally, some generalizations can be made
safely as to the related pharmacological activities of substances that are
close structural congeners.
A. Benzyltetrahydroisoquinolines
(S)(þ)-Reticuline (1) is a dopamine receptor antagonist, blocking the
actions of the dopamine agonist apomorphine, causing decreased
locomotor activity and producing catalepsy in rats (106,107). These
effects seem to be elicited by the blockade of postsynaptic striatal
dopamine receptors (108). Dopaminergic antagonism by reticuline (1)
appears to be rather weak, however, and has not attracted much interest,
although it might be involved in the central depressant effects observed
in rats and mice (109). Reticuline (1) inhibits dopamine uptake and at
high concentrations is toxic to dopaminergic and GABAergic neurons. It
has therefore been suggested that it might be involved in the genesis of
the atypical Parkinsonism of the French West Indies, associated with the
consumption of fruit and infusions of the reticuline-containing Annona
muricata (110). (S)(þ)-Reticuline (1) is also a weak neuromuscular
(nicotinic cholinergic) blocker (111). In addition, it reduces the contractile
force of guinea pig heart by blocking calcium channels (112). (S)
(þ)-Reticuline-induced uterine relaxation and vasorelaxation by L-type
Ca2þ channel blockade have also been demonstrated (113,114). Nevertheless, the cardiovascular effects of reticuline (1) appear to depend on
the blockade of Ca2þ entry and on the inhibition of Ca2þ release from
norepinephrine-sensitive intracellular stores, and by cholinergic (muscarinic) stimulation and nitric oxide synthase activation in the vascular
endothelium (115).
(S)(þ)-Reticuline (1) has antiplatelet aggregation activity (116). It
shows some antifungal activity (117), and is rather weakly antiplasmodial (118). It is also claimed to accelerate hair growth (119).
Reticuline, at 20 mg/kg, administered intraperitoneally, is significantly antinociceptive in the acetic acid-induced mouse writhing test,
and quenches diphenylpicrylhydrazyl (DPPH) radicals with a scavenging concentration (SC50) of 47 mg/mL (143 mM) (120). The latter
antioxidant property could well be related to its effects on inflammation
and pain.
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Nothing is known about the pharmacology of N-oxycodamine (2) or,
in fact, of other benzyltetrahydroisoquinoline N-oxides.
B. Bisbenzylisoquinoline
Isochondodendrine (3) was mentioned more than 50 years ago as a
possible agent for the treatment for dysmenorrhea, but this lead does not
seem to have been pursued (121,122). The only recent work found refers
to the potent antiplasmodial activity of isochondodendrine (3) in vitro
(IC50¼0.10 mg/mL) (123,124), which makes one wonder if D. furfuracea
might be used to treat fever or, more specifically, malaria, in the area
where it grows.
C. Berbinoids
Discretamine (4) is a potent a1-adrenergic blocker, comparable in potency
and basic pharmacology to the hypotensive drug phentolamine. It also
blocks a2-adrenoceptors and 5-HT2 serotonin receptors, at several times
higher concentrations, and seems to be devoid of action at acetylcholine,
histamine, leukotriene, thromboxane, prostaglandin F2a, or angiotensin II
receptors (125). Its action on a1-adrenoceptor subtypes is selective for a1D
over a1A and a1B (126). Discretamine (4) antagonizes the contraction of
human hyperplastic prostate tissue elicited by phenylephrine, electrical
stimulation, or high Ca2þ (127). Its antiplatelet aggregation effect is
another potential beneficial action of this alkaloid (128). Discretamine (4)
is hypotensive in rats at doses between 0.01 and 10 mg/kg. A series of in
vitro experiments suggests that the hypotensive effect of discretamine (4)
is probably due to peripheral vasodilation related to nitric oxide release
from the vascular endothelium (34).
Of all the berbine alkaloids recorded as Duguetia constituents, THP (7)
is by far the most studied in relation to its pharmacology, probably
because its (S)( )-enantiomer (rotundine) and the racemic mixture are
active constituents of the Asian drugs Stephania rotunda and Corydalis
racemosa, respectively. As far back as 1970 (S)-THP, with the generic name
‘‘gindarin,’’ was evaluated for dermatological use in the treatment of
neurodermatitis and alopecia areata, but this study does not seem to
have progressed any further (129).
(7)-THP (7) is listed in the Chinese Pharmacopoeia as an analgesic
with sedative hypnotic effects. This alkaloid, together with its close
analogs tetrahydroberberine and tetrahydrocoptisine, though apparently
not tetrahydrojatrorrhizine (5), were shown to exhibit central depressant
effects in mice and rats similar to those of the well-known neuroleptic
chlorpromazine, leading to the suggestion that these berbines might
represent ‘‘a new type of tranquilizer’’ (130). (7)-THP (7) was later
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recognized as a dopamine, and, to a lesser extent, noradrenaline and
serotonin depletor with an action similar to reserpine (131). In the former
Soviet Union, the S-enantiomer, ‘‘gindarin,’’ was subjected to a
preclinical study (in rats) in the framework of its possible use as a
tranquilizer (or neuroleptic), and was found to be embryotoxic (132).
(S)-THP (7) was subsequently shown to be a dopamine antagonist, while
the R-isomer appears to be responsible for dopamine depletion (133,134),
acting on both pre- and postsynaptic receptors (135). These dopaminergic
actions probably explain the neuroleptic-like activity of both (S)- and
(7)-THP (7). Radioligand displacement studies showed that (S)( )-THP
(7), but not its enantiomer, has affinity for D2(-like) receptors (136).
Subsequently, in vivo data were acquired showing that this alkaloid lacks
agonistic effects (137). It has been shown recently that (S)( )-THP (7)
binds with high affinity (Ki¼94 nM) to rat D1 dopamine receptors, while a
3:1 mixture, in which the R-enantiomer predominates, has only
micromolar affinity (138).
(7)-THP (7) decreases motor activity in rats, producing rigidity (or
catalepsy?) at higher doses, apparently due to enhanced turnover of
dopamine, although increased turnover is also observed for norepinephrine and, at higher doses, for serotonin (139). The antinociceptive
action of (S)( )-THP (7) is attributed to its D2 antagonism in the striatum
and nucleus accumbens, thus enhancing the activity of the brainstem
descending pain modulation system (140 142). This effect might be
reinforced by endogenous opioid release, as chronic administration of
the alkaloid increased the Leu-enkephalin content in the rat striatum
(143), and lesion of a predominantly b-endorphin pathway abolished the
analgesic action of (S)-THP (7) (144). The hypotensive and heart rateslowing effects of (7)-THP (7) have also been related to D2 antagonism
(145). Nevertheless, other mechanisms are clearly at work in the
cardiovascular actions of this alkaloid, whether the S isomer or the
racemic mixture. Calcium channel blockade and a1 and a2 adrenoceptor
antagonism were first implicated in 1989 (146). (S)-THP (7) is also a
subtype nonselective a-adrenoceptor antagonist (147). Experiments in
rats demonstrated the protective effects of the S-enantiomer in experimental myocardial infarction, apparently related to its action on calcium
channels (148,149). The first clinical results showing the effectiveness of
(S)( )-THP in patients with atrial fibrillation or paroxysmal tachyarrhythmias were published in 1993 (150,151). (7)-THP (7) is used for the
treatment of pain, but reports have surfaced of severe cardiac and
neurological toxic effects from abuse of this drug, and it has been
suggested that these problems are also due to calcium channel blockade
(152). Although the peripheral effects on calcium channels and
adrenergic receptors are supported by later studies, there are strong
indications that the cardiovascular effects of (7)-THP (7) are due, at least
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in part, to hypothalamic dopamine antagonism and/or 5-HT2 serotonergic agonism (153,154). The racemic mixture also induces hypothermia,
which is attenuated by brain serotonin depletion or 5-HT2 serotonergic
receptor activation, again indicating a central serotonin antagonist action
of the drug (155).
Pretreatment with (7)-THP (7) suppresses behavioral activation by
picrotoxin (a noncompetitive GABAA receptor inhibitor) in rats,
suggesting that this alkaloid might suppress epileptic seizures through
inhibition of dopamine release (156). In this connection, the alkaloid was
tested on the development of seizures in animals with electrically
kindled amygdala, and found to be very effective as an antiepileptogenic
and anticonvulsant agent in this model (157). It was subsequently shown
that THP (7) is a positive allosteric modulator of GABAA receptors, thus
sharing some of the pharmacological properties of the antiepileptic
barbiturates and benzodiazepines (158). An independent study showed
that orally administered (7)-THP (7) exhibits anxiolytic-like actions in
mice, and that these effects are abolished by coadministration of a
benzodiazepine antagonist, suggesting that THP interacts with the
benzodiazepine site of the GABAA receptor (159).
In rats, (S)( )-THP (7) inhibits methamphetamine- and cocaineinduced conditioned place preference, a preliminary test of possible
antiaddictive activity in humans (160,161). Furthermore, it reduces
cocaine self-administration and reinstatement, suggesting that it could
also be useful in the treatment of cocaine addiction (162,163). Studies in
rodents and in humans suggest that (S)( )-THP (7) can ameliorate opioid
drug craving and increase abstinence (164 165).
THP (7) is a weak inhibitor of the mitochondrial respiratory chain
(166), and binds poorly to DNA (dissociation constants of the order of
10 4 M, with the R-enantiomer binding about twice as strongly as the Senantiomer) (167). In line with these results, THP (7) and also xylopinine
(12) are only weakly cytotoxic (168).
Other miscellaneous effects of THP (7) have been examined in
relatively little detail. The racemic alkaloid produces significant
decreases in thyroid function in hyperthyroid rats, apparently by
inhibiting the release of thyrotropin-stimulating hormone (169). (7)-THP
(7) attenuates several parameters related to neuronal damage caused by
heatstroke in rats (170). (S)-THP (7) has several beneficial actions during
acute cerebral ischemia-reperfusion in rats (171 174), and depresses the
expression of adhesion molecules induced by lipopolysaccharides,
suggesting that it might be useful in the treatment of inflammation
(175). In this connection, and considering that free radicals are involved
in inflammation, it should be pointed out that THP (7) exhibits
antioxidative activity of similar potency to phenolic flavonoids in the
lipid peroxidation and hemolysis assays (176). The racemic alkaloid
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protects against carbon tetrachloride-induced liver damage in mice,
which is also related to the formation of free radicals (177). THP (7)
causes paralysis in the domestic fowl parasitic worm Raillietina
echinobothrida at 1, 2, and 5 mg/mL, apparently related to disturbance
of the nitric oxide signaling pathway (178).
The antiplasmodial activity of thaicanine (14) was demonstrated
almost two decades ago, at low-to-submicromolar concentrations,
against the chloroquine-sensitive Plasmodium falciparum D-2 strain and
the resistant W-2 strain (120). Discretine (10) inhibits the growth of
P. falciparum (chloroquine-resistant FcB1/Colombia strain) with IC50¼
1.6 mM, and is practically noncytotoxic against KB cells (179). THP (7)
and xylopinine (12) are only weakly active against P. falciparum (IC50¼32
and 52 mM, respectively) (180).
D. Protoberberines
Jatrorrhizine (15), only isolated to date, in the Annonaceae, from
D. trunciflora, is mentioned in a large number of pharmacological papers.
Jatrorrhizine (15) lowers arterial blood pressure in normotensive dogs
(181). It blocks a1 and a2 adrenergic receptors with moderate potency and
exhibits some antihypertensive and heart rate-slowing activity in rats,
although at higher concentrations these effects are reversed (182).
Jatrorrhizine (15) inhibits both monoamine oxidase isoforms (MAO-A
and MAO-B) of rat brain with IC50 values of 4 and 62 mM, respectively
(183). It also inhibits rabbit platelet aggregation in vitro (184), and
acetylcholinesterase inhibition by jatrorrhizine (15) has also been
reported (185).
Antimicrobial activity of jatrorrhizine (15) against Mycobacterium
smegmatis was demonstrated at concentrations of less than 100 mg/mL
(184). It was recently tested against a panel of human dermatophytes and
yeast-like fungi, exhibiting minimal inhibitory concentrations (MIC)
between 62.5 and 125 mg/mL against Epidermophyton, Trichophyton, and
Microsporum species, and 250 and 500 mg/mL against Candida tropicalis
and Candida albicans, respectively; all better results than those obtained
with berberine. However, it was inactive against Scopulariopsis brevicaulis
(186). Bifonazole and fluconazole were used as positive controls, the
former exhibiting MIC values above 100 mg/mL for all strains, but
Epidermophyton floccosum, and the latter also, with the additional
exception of Trichophyton rubrum. Tests against 20 strains of Staphylococcus
(including 14 of S. epidermidis) and 20 strains of Propionibacterium acnes,
and 20 Candida strains (including 17 of C. albicans) showed that the
antibacterial potency of jatrorrhizine (15) is less than that of berberine,
and that both alkaloids are inferior to commonly used antibacterial
drugs. However, jatrorrhizine (15) may be a good lead for the
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development of more effective antifungal agents than those in current
use (187).
This alkaloid (15 is active) in vitro against two different clones of
P. falciparum with IC50 values of 0.422 and 1.607 mg/mL, potencies
comparable to that of quinine, however, in an in vivo (mouse) screen
against Plasmodium berghei it was inactive (188). Against the P. falciparum
multidrug-resistant strain K1, it exhibited IC50¼3.15 mM, (corresponding
to 1.1 mg/mL), and showed very modest activity against Entamoeba
histolytica (189). In cultures of Babesia gibsoni, an important parasite in
dogs and a member of a genus causing babesiosis in other carnivores,
ruminants, and horses, jatrorrhizine (15) inhibited growth at low-tomoderate concentrations (190). Dehydrodiscretine (16) inhibits the
growth of P. falciparum with IC50¼0.64 mM (multidrug-resistant K1 strain)
(189), and 0.9 mM (chloroquine-resistant FcB1/Colombia strain) (179).
Jatrorrhizine (15) and dehydrodiscretine (16) have negligible
cytotoxicity against KB cells (179,189). The interaction of jatrorrhizine
(15) with DNA resembles that of ethidium bromide, the classical
DNA intercalator (191). Binding to calf thymus DNA reveals two
different binding sites with dissociation constants of about 25 and
35 mM (192). Binding to the double-stranded oligodeoxynucleotide d
(AAGAATTCTT)2 shows both 1:1 and 1:2 stoichiometries, with similar
affinity to that of palmatine, and greater than those of coptisine or
berberine (absolute values were not determined) (193). Similar studies
with different sequences indicated that the affinity of jatrorrhizine (15)
was reduced for d(AAGGATCCTT)2 and d(AAGCATGCTT)2 relative to
the other protoberberine alkaloids tested (194). Finally, using competitive ethidium bromide displacement experiments on calf thymus
DNA and synthetic double-stranded polynucleotides, the higher
affinity of jatrorrhizine (15) relative to palmatine and berberine and
their preference for AT-rich DNA were confirmed (195). In an
eukaryotic test model (Euglena gracilis vs. the direct-acting mutagen
acridine orange), jatrorrhizine (15) exhibited weak antimutagenic
activity (196).
Jatrorrhizine (15) was shown to be a weak scavenger of DPPH
radicals, and a modest inhibitor of lipid peroxidation in unilamellar
dioleyl-phosphatidylcholine liposomes (197). It downregulates tumor
necrosis factor alpha (TNFa) and E-selectin expression, and decreases the
content of thromboxane B(2) in rat intestinal microvascular endothelial
cells, suggesting that it might reduce inflammatory response by affecting
cytokines and autacoids (198,199), rather than by virtue of its poor
antioxidant properties.
Single doses of 50 and 100 mg/kg jatrorrhizine (15) decreased blood
glucose in normal and alloxan-diabetic mice and increased succinate
dehydrogenase activity in the liver, however, it had no effect on blood
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lactic acid or liver lactate dehydrogenase. The alkaloid also decreased
liver glycogen in normal mice, suggesting that its hypoglycemic activity
can be attributed to increased aerobic glycolysis (184). Several methods
have been used to study the binding of jatrorrhizine (15) to human serum
albumin, concluding that the protein’s secondary structure is altered and
hydrophobic and electrostatic interactions play a major role (200).
Pseudopalmatine (17) does not seem to have been studied pharmacologically.
E. Glaziovine (19)
In the early 1970s the pharmacology of glaziovine (19) was explored by
an Italian pharmaceutical company that registered it as a tranquilizer
under the trademark Suavedols. Its psychopharmacology was compared
with that of diazepam in a double-blind clinical trial (201), and its human
pharmacokinetic parameters were studied (202). In addition, it was
reported to possess anti-gastric ulcer properties in rodents and in
humans (203,204). No studies appear to have addressed its mechanisms
of action as either an anxiolytic or antiulcerogenic agent.
More recently, glaziovine (19) was evaluated for anti-hepatitis B virus
activity. This alkaloid proved to be highly potent, as judged by its IC50
value of 8 mM, as an inhibitor of HBV surface antigen production. The
corresponding value for the positive control, the anti-HBV drug 3TC or
Lamivudine, was 11.7 mM. However, glaziovine (19) was more toxic to
uninfected that to infected cells (205).
The isolated yield of glaziovine (19) from D. vallicola leaves was
0.27%, placing this abundant and easily accessible material in a good
position as a source of a useful plant drug (26). Glaziovine (19) is one of
60 alkaloids listed as having particular pharmaceutical and biological
significance (206).
F. Aporphines
Anonaine (3) relaxes rat aorta and tail artery precontracted with
noradrenaline, predominantly through adrenergic receptors. Since its
affinity for L-type Ca2þ channels is an order of magnitude less for a1
adrenoceptors in rat cerebral cortical membranes, it does not contribute
to intracellular mobilization of Ca2þ, and its effect on phosphodiesterases
is negligible. It is also slightly selective for a1A and a1D adrenoreceptors
relative to the a1B subtype, as determined by radioligand competition
experiments (207,208).
Xylopine (28) is a selective a1 (vs. a2) adrenergic receptor antagonist with submicromolar functional potency (209). In the rabbit
oviduct, isocorydine (41) inhibits spontaneous and noradrenaline-elicited
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Edwin G. Pérez and Bruce K. Cassels
contractions, indicating that this alkaloid is an adrenoceptor antagonist
(210). A further study in a rat aorta model suggested that the effect is
mediated primarily through a1 adrenoceptors (211). The effects of
isocorydine (41) on the action potentials of canine heart muscle cells have
also been studied in vitro (212).
Asimilobine (20) inhibits rabbit aortal contractions induced by 10 6 M
serotonin with pA2¼5.78, suggesting that this alkaloid is a 5-HT2
serotonin receptor antagonist (213). Dicentrine (39) inhibits the contraction of rat stomach muscle strips induced by serotonin, histamine, Kþ,
and Ca2þ in a noncompetitive manner. In the case of serotonin-induced
contractions, the relaxation depends on Ca2þ release from intracellular
stores, suggesting that 5-HT (presumably 5-HT2B) receptors are involved
(214). Asimilobine (20), nornuciferine (22), and anonaine (23) bind to
5-HT1A serotonin receptors with low micromolar IC50 values versus [3H]
rauwolscine, and were shown to be full agonists (215). In [3H]8-hydroxy2-(di-N-propylamino)tetralin displacement experiments, N-methyllaurotetanine (37) exhibits high affinity for 5-HT1A receptors (Ki¼85 nM,
pKi¼7.07) (216).
Isoboldine (38) relaxes isolated guinea pig trachea with IC50¼710 mM,
suggesting a b-adrenoceptor-mediated mechanism (217). Dicentrine (39)
has been extensively studied as a cardiovascular agent. It was first shown
to be a potent a1-adrenoceptor antagonist (less potent than prazosin, and
more potent than phentolamine) with little effect on b-adrenergic
receptors (218,219). Its hypotensive effect was demonstrated in vivo in
rats by the intravenous and oral routes, and in conscious, spontaneously
hypertensive animals, oral administration of 5 and 8 mg/kg caused
hypotension lasting more than 15 h (220). In rats fed a high-cholesterol
diet, oral administration of dicentrine (39) decreased the mean arterial
pressure (more so in spontaneously hypertensive animals), and reduced
the total plasma cholesterol by reducing the low-density lipoprotein
fraction, and the total plasma triglyceride by reducing the very lowdensity lipoprotein fraction (221).
Experiments in isolated cardiac cells and in rabbit heart showed that
dicentrine (39) blocks sodium and potassium currents, and is a
potentially useful antiarrhythmic agent at doses in the same range as
quinidine (222,223). The effects of dicentrine (39) on the mechanical
properties of systemic arterial trees have been studied in dogs (224).
Dicentrine (39) inhibits serum-stimulated kidney mesangial cell proliferation in the rat, and was therefore viewed, together with other
vasodilators, as an agent with the potential to delay the progression of
chronic glomerulopathy (225). As an a1-adrenoceptor antagonist it also
inhibits contractions of human hyperplastic prostate elicited by
adrenergic stimulation, and might therefore be of use to relieve bladder
outlet obstruction in patients with benign prostatic hyperplasia (226).
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Anonaine (23) and isopiline (24) inhibit dopamine uptake by rat
striatal synaptosomes with IC50¼0.8 and 2.5 mM, respectively. Anonaine
(23) is a selective uptake inhibitor relative to its affinities for D1-like and
D2-like dopamine receptors as determined in radioligand displacement
experiments (IC50 vs. [3H]SCH23390 and [3H]raclopride: 68 and 19 mM,
respectively; ratios of uptake to receptor binding IC50 values: 85.0 and
23.5), while isopiline (24) exhibits much lower selectivity (D1-like and D2like binding IC50: 10 and 34 mM, respectively; IC50 ratios 3.0 and 13.6)
(227).
Asimilobine (20), in the 0.05 0.2 mM range, reduces intracellular
dopamine in PC12 cells for 24 h with IC50¼0.13 mM. At this concentration
it decreases the activities of tyrosine hydroxylase (TH, by 73.2% and for a
longer time) and aromatic L-amino acid decarboxylase, and reduces TH
mRNA and intracellular cAMP levels. Alone, it does not alter PC12 cell
viability at concentrations up to 5 mM. However, in association with
L-DOPA asimilobine (20) inhibits the L-DOPA-induced increase in
dopamine levels and enhances L-DOPA cytotoxicity (228).
N-Methylasimilobine (21) is a significant inhibitor of platelet
aggregation elicited by collagen, arachidonic acid (AA), and plateletactivating factor (PAF). Xylopine (28) and N-methyllaurotetanine (37)
inhibit platelet aggregation with different potencies depending on
the substance used as an aggregation inducer in each case (229).
Dicentrine (39) also inhibits platelet aggregation induced by AA,
collagen, adenosine diphosphate (ADP), PAF, thrombin, or the synthetic
U46619, and induces ATP release from platelets. Additional experiments
indicated that these effects are due to the inhibition of thromboxane B2
formation and increased cAMP levels (218,230,231).
N-Methyllaurotetanine (37), administered intravenously, is antihyperglycemic in normal and streptozotocin-induced diabetic rats (232).
N-Methyllaurotetanine (37) and norisocorydine (40), at 20 mg/kg i.p., are
significantly antinociceptive in the acetic acid-induced mouse writhing
test, and quench DPPH radicals with SC50¼28 and 14 mg/mL (82 and
43 mM), respectively (25,120). Antinociceptive activity is often associated
with free radical inactivation, and in this regard it should be mentioned
that anonaine (23) was one of the first aporphine alkaloids for which
antioxidative activity was demonstrated (233).
Anonaine (23) reduces the viability of normal rat hepatocytes,
and HepG2 and HeLa tumor cells, with IC50 values of 70.3, 33.5, and
24.8 mg/mL, respectively, in 24-h experiments (234). Non-cancer Vero and
MDCK cells exposed to 100 mM anonaine (23) for 24 h experienced
reduced viability by about 25% and 5%, respectively (235). In the case of
HeLa cells, the decrease amounted to 77%, and was associated with DNA
damage and a dose-related block of the cell cycle before the G1 phase.
These effects were correlated to increased intracellular nitric oxide,
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Edwin G. Pérez and Bruce K. Cassels
reactive oxygen species, glutathione depletion, disruption of the
mitochondrial transmembrane potential, activation of caspases 3, 7, 8,
and 9, and poly(ADP-ribose) polymerase (PARP) cleavage with upregulation of Bax and p53 proteins (235).
Dicentrine (39) inhibits the growth of murine leukemia P388 and
L1210, melanoma B16, bladder cancer MBC2, and colon cancer Colon 26
cells in culture, and also reduces mitogen-induced lymphocyte proliferation and the growth of IL-dependent CTLL2 cells (236). It slows the
growth of the human hepatoma cell line HuH-7 and decreases the
efficiency of colony formation by these cells and the MS-G2 line, and
strongly inhibits DNA and RNA synthesis. Additional evaluations in 21
tumor cell lines showed that dicentrine (39) was particularly cytotoxic to
esophageal carcinoma HCE-6, lymphoma Molt-4 and CESS, leukemia
HL60 and K562, and hepatoma MS-G2 (237). This alkaloid is active in a
DNA unwinding assay, and is a modest inhibitor of topoisomerase II
(IC50¼27 mM) (238). However, it shows no antiproliferative activity
versus several yeast strains (239). Duguetine (76) ‘‘caused considerable
antitumoral activity’’ (240).
An extract of D. odorata was found to inhibit the G2 DNA damage
checkpoint, a target that is expected to enhance the effectiveness of
DNA-damaging anticancer therapy. Dehydrodiscretine (16), pseudopalmatine (17), oliveroline (60), and N-methylguatterine (66), were isolated
by bioassay-guided fractionation following this bioactivity, however,
only oliveroline (60) had confirmed, though modest, potency (at
concentrations above 10 mM), and was isolated in sufficient amounts for
additional testing (14).
Pachystaudine (82) interferes with the replicative cycle of herpes
simplex virus type 1 (HSV-1) (241).
Anonaine (23) and xylopine (28) are weakly antibacterial and antifungal
(120,242,243), and anolobine (27) is only active against Gram-positive
bacteria and Mycobacterium phlei in the 10 4 molar range with
MIC90¼12 50 and 6 25 mg/mL, respectively (243). Anolobine (27) induces
chromosomal aberrations in a Chinese hamster lung cell line at concentrations as low as 2.5 mg/mL (244). At 300 mg/mL, dicentrine (39) showed
‘‘moderate’’ to ‘‘good’’ activity against the fungi Microsporum canis,
Microsporum gypseum, Trichophyton mentagrophytes, and E. floccosum, but
was inactive against C. albicans, Aspergillus niger, and Penicillium sp. (245).
Nornuciferine (22) and xylopine (28) are significantly active against
Leishmania mexicana and Leishmania panamensis, with the latter alkaloid
showing LD50¼3 mM, vs. L. mexicana, and 37-fold higher toxicity towards
the parasite than towards the host cells, the macrophages (246).
Dicentrine (39) is active against Trypanosoma brucei brucei in vitro with
IC50¼3.15 mM (247). Duguetine (76) is moderately active against the
trypomastigote form of Trypanosoma cruzi (IC50¼9.32 mM) (120).
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Asimilobine (20), anonaine (23), xylopine (28), isolaureline (29), and
dicentrine (39) are antiplasmodial at low-to-micromolar concentrations
against the chloroquine-sensitive P. falciparum D-2 strain and the resistant
W-2 strain, but under the same conditions chloroquine has 1.3 and
11.2 nM ED50 values against the sensitive and the resistant strains,
respectively (248). Isocorydine (41) is moderately active in vitro against
P. falciparum, with IC50¼37 mM, and practically noncytotoxic and inactive
against E. histolytica (193). Oliveroline is active against P. falciparum at low
micromolar concentrations (27).
Dicentrine (39) reduces the motility of Haemonchus contortus larvae
(the large stomach worm of ruminants), with EC90¼6.3 mg/mL, and an
oral dose of 25 mg/kg in mice reduced the worm count by 67% (249).
G. Oxoaporphines
Atherospermidine (86) relaxes uterine contractions induced by high Kþ
and by oxytocin, with a mechanism involving Ca2þ entry and release
from intracellular stores (250). Liriodenine (83), in the 10 7 10 4 M
range, relaxes rat aorta contracted with potassium chloride or norepinephrine, but in Ca2þ-free medium it does not inhibit the response
elicited by caffeine, indicating that its vasorelaxant action is mediated by
interaction with a1 adrenergic receptors and voltage-operated calcium
channels (251). Dicentrinone (91) was also shown to possess weak
vasorelaxant activity (252). Liriodenine (83) appears to regulate dopamine biosynthesis in the 5 10 mM range by reducing TH gene expression
and activity, and is protective against L-DOPA-induced cytotoxicity in
PC12 cells (253).
At 100 mM liriodenine (83) inhibits platelet aggregation, particularly
that elicited by ADP or collagen, and less by AA or PAF, with
aggregation falling to 5.4%, 5.3%, 40.5%, and 84.1% of controls,
respectively (229,252). Lanuginosine (87) shows similar activity to
liriodenine (83) (254).
Liriodenine (83) is cytotoxic to KB, A-549, HCT-8, and L-1210 tumor
cells (255,256). It is also a mutagen for Salmonella typhimurium TA100 (257).
Chromosomal aberrations are induced by liriodenine (83) at 5 mg/mL
(244). Liriodenine (83) is selectively toxic against DNA repair- and
recombination-deficient yeast mutants (IC12¼16.7 mg/mL vs. the rad 52
mutant), a model in which lysicamine (84) and O-methylmoschatoline
(85) are inactive. The selectivity of liriodenine (83) suggested that its
activity might be mediated by topoisomerase inhibition (258). Topoisomerase II inhibition by liriodenine (83) was confirmed in CV-1 cells
infected with simian virus 40 (SV40), and it was also shown that this
alkaloid is not a substrate for the verapamil-sensitive drug efflux pump
(a mechanism underlying drug resistance) in CV-1 cells (248). Liriodenine
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Edwin G. Pérez and Bruce K. Cassels
(83) exhibits moderate antiproliferative activity versus the human breast
cancer cell lines MCF-7, the doxorubicin-resistant MCF-7/ADR, and the
estrogen receptor-deficient MDA-MB435 and MT-1 lines, with IC50¼15.6,
16.7, 16.4, and 18.2 mM, respectively (259). In another study versus MCF-7,
NCI-H460, and SF-268 cell lines, IC50 values of 3.19, 2.38, and 2.19 mg/mL,
respectively, were recorded (260). It should be pointed out that 3.19 mg/
mL corresponds to 11.6 mM, in good agreement with the earlier value. In
A594 human lung cancer cells, liriodenine suppresses proliferation doseand time-dependent in the 2 20 mM range, mainly through cell cycle
inhibition (G2/M arrest) and induction of apoptosis (261). Human
hepatoma cell lines bearing the wild-type p53 oncogene (Hep G2 and
SK-Hep-1) have also been challenged with liriodenine (83), which
induced cell cycle arrest in the G1 phase and inhibited DNA synthesis,
increasing the expression of p53 and inducible nitric oxide synthase, and
the intracellular NO level (262).
Lysicamine (84) is a modest inhibitor of the proliferation of two
human liver cancer cell lines (Hep G2 and Hep 2,2,15) with IC50¼8.4 and
3.4 mg/mL, respectively (56). Dicentrinone (91) showed selective antiproliferative activity against some yeast strains, but not others. When tested
against recombinant human topoisomerase I it only inhibited the enzyme
to a small extent, stabilizing the enzyme DNA binary complex (239).
Apparently, the earliest recorded biological activities of liriodenine
(83) are antibacterial and antifungal, which it shares with lysicamine (84)
(243,263,264). When mice infected with a lethal dose of C. albicans were
treated with liriodenine (and also its methiodide), the proliferation of the
pathogen was reduced significantly (265). The moderate activity of
liriodenine (83) and O-methylmoschatoline (85) was demonstrated again
more recently against several different fungi and bacteria (266,267).
Liriodenine (83) was claimed to be a fairly potent growth inhibitor of
Leishmania major and Leishmania donovani, showing inhibition at 3.12 mg/
mL (11.3 mM) (268), although another group reported IC50¼26.16 mM for a
possibly different strain of L. donovani (269). A more recent study using
Leishmania brasiliensis and Leishmania guyanensis promastigotes gave
IC50¼58.5 and 21.5 mM, respectively, with O-methylmoschatoline (85)
being about five times less active (270). Lysicamine (84) is also active
against L. mexicana (245). Dicentrinone (91) is reported to have unusually
potent leishmanicidal activity (IC50¼0.01 mM) (240). O-Methylmoschatoline inhibits the growth of Trypanosoma brucei at 6.25 mg/mL (268).
Liriodenine (83) is active against P. falciparum with IC50¼15 mM (269,271).
H. Aminoethylphenanthrenes
Atherosperminine (94) produces behavioral stereotypy, increased
spontaneous motor activity and amphetamine toxicity, reversal of
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haloperidol-induced catalepsy, inhibition of conditioned avoidance
response, inhibition of morphine analgesia, and potentiation of the
anticonvulsant action of diphenylhydantoin, effects associated with
dopamine receptor stimulation (272). It also inhibits the contraction of
guinea pig trachealis muscle elicited by carbachol, prostaglandin F2a, a
synthetic thromboxane analogue and leukotriene C4, it potentiates
tracheal relaxation and cAMP accumulation elicited by forskolin and, at
higher concentrations, by itself raises the content of cAMP, but not cGMP, in
the tissue. Thus, its major mechanism of action seems to be the inhibition of
cAMP phosphodiesterase (273).
At 100 mg/mL, atherosperminine (94) and its N-methyl quaternary
salt completely inhibited platelet aggregation elicited by ADP, AA,
collagen, or PAF, while atherosperminine N-oxide (95), though inhibiting
AA- and collagen-induced aggregation, is less effective against aggregation elicited by ADP or PAF. At this dose, atherosperminine (94) and its
N-oxide are also complete antagonists of high potassium or norepinephrine-induced contractions of rat thoracic aorta, pointing to simultaneous a1-adrenoceptor and calcium channel inhibition (274).
I. Copyrine Alkaloids
Sampangine (97) potently inhibits HL-60 human leukemia cell proliferation by 50% at IC50¼2.65 mM, and its (lethal) DC50 value is 24.5 mM,
suggesting that apoptosis plays a role in the cytotoxicity of this alkaloid,
as confirmed by its effect at 20 mM on caspase-3 activity. At 4.0 mM
sampangine induces cell cycle arrest in the G0/G1 phase, and at 20 mM
leads to accumulation of cells with decreased DNA, typical of apoptotic
cells. Low and high concentrations of sampangine (97) caused opposite
effects on the potential of mitochondrial membranes, leading first to
hyperpolarization (275). Treatment of HL-60 cells with sampangine (97)
induced the rapid formation of reactive oxygen species, and quenching
these with antioxidants abolished the pro-apoptotic activity of the
alkaloid, indicating that sampangine-induced oxidative stress plays a key
role in DNA damage (276). Sampangine (97) strongly inhibits the
proliferation of human malignant melanoma cells (SK-MEL) with
IC50¼0.37 mg/mL but, as observed previously in the HL-60 model, it is
at least ten times less potent than other human cancer cells in culture (KB,
BT-549, and SK-OV-3) (16).
Hadranthine A (99) was practically inactive against the human cancer
cells tested, but hadranthine B (100) inhibited the proliferation of
SK-MEL, KB, BT-549, and SK-OV-3 cells with IC50¼3.0, 6.4, 6.6, and
3.6 mg/mL, respectively. Imbiline-1 (101) inhibited SK-MEL and SK-OV-3
cells with IC50¼2.0 and 5.0 mg/mL, respectively, but showed IC50 values
greater than 10 mg/mL in the other cell lines (16).
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Sampangine (97) and 3-methoxysampangine (98) exhibit antifungal
and antimycobacterial potencies about one half of those of amphotericin
B and rifampicin, with MIC in the 0.78 1.56 mg/mL range against
C. albicans, Cryptococcus neoformans, Aspergillus fumigatus, and Mycobacterium intracellulare, somewhat higher than the data published previously
by these authors for the 3-methoxy derivative (277,278). In Saccharomyces
cerevisiae, sampangine (97) induces oxidative stress, and its antifungal
activity is at least partially due to alterations in heme metabolism (279).
Sampangine (97), 3-methoxysampangine (98), hadranthine A (99),
and imbiline-1 (101), but not hadranthine B (100), exhibit antiplasmodial
activity in vitro against P. falciparum (chloroquine-resistant clone W-2 and
chloroquine-sensitive clone D-6). Although about ten times less potent
than chloroquine against the D-6 clone, hadranthine A (99) shows
reasonably good selectivity (selectivity index W40) versus Vero cells,
while the other alkaloids are even less potent and less selective. On the
other hand, sampangine (97) and 3-methoxysampangine (98) are more
potent than chloroquine against the chloroquine-resistant W-2 clone (16).
J. 1-Aza-9,10-anthraquinones
Cleistopholine (104) inhibits the proliferation of Hep G2 and Hep 2,2,15
human hepatocarcinoma cell lines, with IC50¼0.22 and 0.54 mg/mL,
respectively (56). It has modest antifungal and antimycobacterial
activities with MIC against C. albicans, C. neoformans, A. fumigatus, and
M. intracellulare of 12.5, 1.56, 100, and 12.5 mg/mL, respectively (277), and
has also shown activity against mutant S. cerevisiae strains, Cladosporium
cladosporioides, and Cladosporium sphaerospermum (54). Cleistopholine (104)
inhibits the growth of P. falciparum at low micromolar concentrations (27).
VII. CONCLUDING REMARKS
The foregoing sections illustrate a cyclic trend that has been developing
for a long time in natural products research, but which seems to take on
specific features in studies on plant families that are traditionally seen as
rich sources of alkaloids. In its initial century, from the isolation of
morphine and quinine through mescaline, alkaloid chemistry was largely
motivated by the desire to understand and to better apply the medicinal
or biological properties of plant drugs. Later on, rapid advances in
structure elucidation methodology and instrumentation led to an
approach akin to the mountaineer’s ‘‘Why climb it? Because it’s there!,’’
while biosynthetic work remained more concerned with a quest for
explanations. Over the last few decades a renewed interest in practical
uses fired the development of bioassay-guided fractionation and a
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preference for biosynthetic studies related to commercially or medically
important alkaloids. In the meantime, organic and medicinal chemists
developed synthetic methodology, and used alkaloid structural templates to generate new drugs, and fruitful collaborative efforts continue,
both in the pharmaceutical industry and in academia.
In the specific case of Duguetia, the identification of known alkaloids
and the discovery of new structures have slowed considerably, while the
pharmacology of some of the more widespread constituents has made
surprising progress. But something seems to be lacking. It is most likely
that there is an enormous wealth of ethnopharmacological knowledge
risking oblivion and still waiting to be recorded. If alkaloid chemistry is
to contribute to our understanding of the biology of the genus, it needs to
address a wider range of species, particularly those belonging to
unexplored or little-explored sections, and metabolic profiling should
be applied to many of the plants that have already been studied as well
as those that have not. Bioassay-guided fractionation has yielded some
spectacular results, but what bioassays should be used? Easy antibacterial assays (unlike antifungal or antiparasitic assays) do not seem to have
uncovered anything of interest in higher plants, and natural products
chemists are not usually qualified to identify apparently arcane
biological targets such as some of those now pursued by the
pharmaceutical industry, or to set up the necessary tests, stressing the
need to collaborate with pharmacologists. Although much is known
about the pharmacology of some Duguetia alkaloids commonly found in
other plants, the more characteristic alkaloids such as the 7-oxygenated
and the 9,11-dioxygenated aporphinoids remain practically untouched.
And what about structural modification or analog synthesis?
It is hoped that these comments will stimulate discussion in the
alkaloid chemical community and invigorate research, leading to both
qualitative and quantitative leaps in productivity, and to novel
approaches that will surely have unsuspected, but doubtless very
valuable, results.
ACKNOWLEDGMENTS
This work was supported in part by the Millennium Science Initiative (Chile), ICM P05-001F. Edwin G. Pérez was the recipient of CONICYT Bicentennial Program Postdoctoral
Scholarship, PDA-23.
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